Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors

ABSTRACT

The present application provides pyrazolyl pyrimidinylamine inhibitors of cyclin-dependent kinase 2 (CDK2), as well as pharmaceutical compositions thereof, and methods of treating cancer using the same.

This application claims the benefit of priority of U.S. Prov. Appl. No.62/814,036, filed Mar. 5, 2019, and U.S. Prov. Appl. No. 62/870,465,filed Jul. 3, 2019, each of which is incorporated herein by reference inits entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been filedelectronically in ASCII format and is hereby incorporated by referencein its entirety. Said ASCII copy, created on Mar. 3, 2020, is named20443-0603001_SL.txt and is 15,000 bytes in size.

TECHNICAL FIELD

This application is directed to pyrazolyl pyrimidinylamine compoundswhich inhibit cyclin-dependent kinase 2 (CDK2) and are useful fortreating cancer.

BACKGROUND

Cyclin-dependent kinases (CDKs) are a family of serine/threoninekinases. Heterodimerized with regulatory subunits known as cyclins, CDKsbecome fully activated and regulate key cellular processes includingcell cycle progression and cell division (Morgan, D. O., Annu Rev CellDev Biol, 1997, 13: 261-91). Uncontrolled proliferation is a hallmark ofcancer cells. The deregulation of the CDK activity is associated withabnormal regulation of cell-cycle, and is detected in virtually allforms of human cancers (Sherr, C. J., Science, 1996, 274(5293): 1672-7).

CDK2 is of particular interest because deregulation of CDK2 activityoccurs frequently in a variety of human cancers. CDK2 plays a crucialrole in promoting G1/S transition and S phase progression. In complexwith cyclin E (CCNE), CDK2 phosphorylates retinoblastoma pocket proteinfamily members (p107, p130, pRb), leading to de-repression of E2Ftranscription factors, expression of G1/S transition related genes andtransition from G1 to S phase (Henley, S. A. and F A. Dick, Cell Div,2012, 7(1): p. 10). This in turn enables activation of CDK2/cyclin A,which phosphorylates endogenous substrates that permit DNA synthesis,replication and centrosome duplication (Ekholm, S. V. and S. I. Reed,Curr Opin Cell Biol, 2000, 12(6): 676-84). It has been reported that theCDK2 pathway influences tumorigenesis mainly through amplificationand/or overexpression of CCNE1 and mutations that inactivate CDK2endogenous inhibitors (e.g., p27), respectively (Xu, X. et al.,Biochemistry, 1999, 38(27): 8713-22).

CCNE1 copy-number gain and overexpression have been identified inovarian, gastric, endometrial, breast and other cancers and beenassociated with poor outcomes in these tumors (Keyomarsi, K. et al., NEngl J Med. 2002, 347(20): 1566-75; Nakayama, N. et al., Cancer, 2010,116(11): 2621-34; Au-Yeung, G. et al., Clin Cancer Res, 2017, 23(7):1862-1874; Rosen, D. G. et al., Cancer, 2006, 106(9): 1925-32).Amplification and/or overexpression of CCNE1 also reportedly contributeto trastuzumab resistance in HER2+ breast cancer and resistance toCDK4/6 inhibitors in estrogen receptor-positive breast cancer(Scaltriti, M. et al., Proc Natl Acad Sci USA, 2011, 108(9): 3761-6;Herrera-Abreu, M. T. et al., Cancer Res, 2016, 76(8): 2301-13). Variousapproaches targeting CDK2 have been shown to induce cell cycle arrestand tumor growth inhibition (Chen, Y. N. et al., Proc Natl Acad Sci USA,1999, 96(8): 4325-9; Mendoza, N. et al., Cancer Res, 2003, 63(5):1020-4). Inhibition of CDK2 also reportedly restores sensitivity totrastuzumab treatment in resistant HER2+ breast tumors in a preclinicalmodel (Scaltriti, supra).

These data provide a rationale for considering CDK2 as a potentialtarget for new drug development in cancer associated with deregulatedCDK2 activity. In the last decade there has been increasing interest inthe development of CDK selective inhibitors. Despite significantefforts, there are no approved agents targeting CDK2 to date (Cicenas,1, et al., Cancers (Basel), 2014, 6(4): p. 2224-42). Therefore itremains a need to discover CDK inhibitors having novel activityprofiles, in particular those targeting CDK2. This application isdirected to this need and others.

SUMMARY

The present invention relates to, inter alia, compounds of Formula (I):

or pharmaceutically acceptable salts thereof, wherein constituentmembers are defined herein.

The present invention further provides pharmaceutical compositionscomprising a compound described herein, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides methods of inhibiting CDK2,comprising contacting the CDK2 with a compound described herein, or apharmaceutically acceptable salt thereof.

The present invention further provides methods of inhibiting CDK2 in apatient, comprising administering to the patient a compound describedherein, or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating a human subjecthaving a disease or disorder associated with cyclin-dependent kinase 2(CDK2), comprising administering to the human subject a compounddescribed herein, or a pharmaceutically acceptable salt thereof, whereinthe human subject has been previously determined to: (i) (a) have anucleotide sequence encoding a p16 protein comprising the amino acidsequence of SEQ ID NOT; and/or (b) have a cyclin dependent kinaseinhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acidsubstitutions and/or deletions; (ii) (a) have an amplification of thecyclin E1 (CCNE1) gene; and/or (b) have an expression level of CCNE1 ina biological sample obtained from the human subject that is higher thana control expression level of CCNE1.

The present invention also provides methods of treating a human subjecthaving a disease or disorder associated with cyclin-dependent kinase 2(CDK2), comprising: (i) identifying, in a biological sample obtainedfrom the human subject:

(a) a nucleotide sequence encoding a p16 protein comprising the aminoacid sequence of SEQ ID NOT; and/or (b) a cyclin dependent kinaseinhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acidsubstitutions; (ii) identifying, in a biological sample obtained fromthe human subject: (a) an amplification of the cyclin E1 (CCNE1) gene;and/or(b) an expression level of CCNE1 that is higher than a controlexpression level of CCNE1; and (iii) administering a compound describedherein, or a pharmaceutically acceptable salt thereof, to the humansubject.

The present invention further provides methods of evaluating theresponse of a human subject having a disease or disorder associated withcyclin-dependent kinase 2 (CDK2) to a compound described herein, or apharmaceutically acceptable salt thereof, comprising: (a) administeringthe compound or the salt, to the human subject, wherein the humansubject has been previously determined to have an amplification of thecyclin E1 (CCNE1) gene and/or an expression level of CCNE1 that ishigher than a control expression level of CCNE1; (b) measuring, in abiological sample of obtained from the subject subsequent to theadministering of step (a), the level of retinoblastoma (Rb) proteinphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3, wherein a reduced level of Rb phosphorylation at theserine corresponding to amino acid position 780 of SEQ ID NO:3, ascompared to a control level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3, is indicativethat the human subject responds to the compound or the salt.

The present invention further provides a compound described herein, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound describedherein, or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament for use in any of the methods describedherein.

DESCRIPTION OF DRAWINGS

FIGS. 1A-1B: Characterization of ovarian and endometrial cell lines.FIG. 1A: Cell lines used for study included four cell lines with CCNE1amplification and three cell lines with no CCNE1 amplification. CCNE1amplification copy numbers are indicated. FIG. 1B: The expression ofCCNE1 was determined by Western blot in indicated cell lines. This blotshow cell lines with CCNE1 gain of function by copy number (CN>2)expressed higher levels of CCNE1 protein compared with cell lines withcopy neutral or loss of function of the gene (CN≤2). GAPDH was detectedas a loading control. Non-Amp, non-amplification; Amp, amplification.

FIGS. 2A-2B: siRNA mediated CDK2 knockdown inhibits proliferation inCCNE1 amplified cell lines. FIG. 2A: CCNE1 amplified Fu-ovl (upper) andKLE (lower) cells were harvested and subjected to cell cycle analysis 72hours after transfection with either scrambled siRNAs (“Ctl”) or CDK2siRNAs. The cell cycle phase distribution was evaluated by FACS. Shownare representative images of three separate experiments. FIG. 2B: CDK2knockdown was confirmed by Western blot analysis after transfection withCDK2 siRNA. GAPDH was used as a loading control.

FIGS. 3A-3B: CDK2 knockdown does not inhibit proliferation in CCNE1Non-Amp lines. FIG. 3A: CCNE1 non-amplified COV504 and Igrov1 cells wereharvested and subjected to cell cycle analysis 72 hours aftertransfection with Ctl siRNAs and CDK2 siRNAs. The cell cycle phasedistribution was evaluated by FACS. Shown are representative images ofthree separate experiments. FIG. 3B: CDK2 knockdown was confirmed byWestern blot analysis after transfection with CDK2 siRNA. GAPDH was usedas a loading control.

FIG. 4: CDK2 knockdown by siRNA inhibits proliferation in CCNE1amplified, but not in CCNE1 non-amplified, human cancer cell lines.Percentage of cells at the S phase 3 days after transfection of CDK2siRNAs, relative to Ctl siRNA. The cell cycle phase distribution wasevaluated by FACS. Means represent three independent experiments in fourCCNE1 Amp cell lines and three Non-Amp lines.

FIG. 5: Palbociclib treatment induces dose-dependent inhibition ofproliferation in CCNE1 non-amplified, but not in amplified cell lines.Cell cycle analysis of CCNE1 non-amplified cell line COV504 (upper) andCCNE1 amplified OVCAR3 cells (lower) after Palbociclib treatment for 16hours. The cell cycle phase distribution was evaluated by FACS.

FIG. 6: Palbociclib treatment selectively inhibits proliferation inCCNE1 non-amplified cancer cell lines. Percentage of cells at the Sphase after 16 hours of Palbociclib with the indicated doses, relativeto DMSO.

FIGS. 7A-7B: CDK2 knockdown by siRNAs blocks RB phosphorylation at S780in CCNE1 amplified, but not in non-amplified ovarian cells. FIG. 7A:Four CCNE1 Amp cell lines, COV318, Fu-OV1, OVCAR3 and KLE cells, weretransfected with CDK2 siRNAs for 72 hours. FIG. 7B: Three CCNE1 Non-Ampcell lines, COV504, OV56 and Igrov1, were transfected with CDK2 siRNAsfor 72 hours. The total proteins were extracted from CDK2 siRNA or CtlsiRNA transfected cells and subjected to western blotting. GAPDH wasused as a loading control.

FIGS. 8A-8B: Palbociclib blocks RB phosphorylation at S780 in CCNE1non-amplified, but not in amplified ovarian cells. FIG. 8A: CCNE1 AmpOVCAR3 and COV318 cells were treated at various concentrations ofPalbociclib as indicated for 1 hour or 15h. FIG. 8B: CCNE1 Non-AmpCOV504 and OV56 were treated at various concentrations of Palbociclib asindicated for 1 hour or 15h. The total proteins were extracted fromthese Palbociclib or DMSO (controls) treated cells and subjected towestern blotting. p-RB, phosphorylated retinoblastoma protein. GAPDH wasused as a loading control.

FIGS. 9A-9B: CDK2 degradation by dTAG decreases RB phosphorylation atS780. FIG. 9A: Chemical structure of dTAG. FIG. 9B: CDK2-FKBP12(F36V)degradation by CDK2-dTAG treatment for 14 hours inhibited RBphosphorylation at S780 in CDK2 knockout OVCAR3 (right, Cas9+,CDK2-FKBP12(F36V)-HA+, CDK2-gRNA) cells, but not in OVCAR3 cells withendogenous CDK2 (left, Cas9+, CDK2-FKBP12(F36V)-HA+, Ctl-gRNA).

FIGS. 10A-10B: p-RB S780 HTRF cellular Assay for identification of CDK2inhibitors. FIG. 10A: IC₅₀ in CDK2 biochemical kinase activity assay.FIG. 10B: Concentration response analysis of reference compounds testedin the p-RB S780 HTRF cellular assay. HTRF, homogeneous time-resolvedfluorescence. IC₅₀ from HTRF cellular Assay correlates with IC₅₀ in CDK2enzymatic assay.

FIG. 11: Bioinformatics analysis of CCLE dataset reveals the sensitivityto CDK2 inhibition in CCNE1 amplified cells relies on functional p16.FIG. 11 shows the status of p16 in CDK2 sensitive verse insensitive celllines. CCLE: Broad Institute Cancer Cell Line Encyclopedia (seeBarretina, below).

FIGS. 12A-12B: CCNE1 amplified cells with dysfunctional p16 do notrespond to CDK2 inhibition. FIG. 12A: Western blot analysis of p16 inthree gastric cell lines with CCNE1 Amp. FIG. 12B: Percentage of cellsat the S phase 3 days after transfection of CDK2 siRNAs, relative to CtlsiRNA. The cell cycle phase distribution was evaluated by FACS.

FIG. 13: p16 knockdown by siRNA abolishes CDK2 inhibition induced cellcycle suppression in CCNE1 amplified cells. The percentage of S phasecells following p16 knockdown and CDK2 inhibitor treatment, normalizedto cell with Ctl siRNA and DMSO treatment. CCNE1 amplified COV318 cellswere transfected with either Ctl siRNAs or p16 siRNA. 72 hours aftertransfection, cells were treated with 100 nM CDK2 inhibitor Compound A.Cells were harvested and subjected to cell cycle analysis 16 hours aftertreatment.

DETAILED DESCRIPTION Compounds

The present application provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

n is 1, 2, 3, 4, 5, or 6;

o is 1, 2, 3, or 4;

p is 1, 2, 3, or 4;

R¹ is selected from halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, and C₃₋₄ cycloalkyl; and R² is selected from H, D, halo,CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₃₋₄cycloalkyl; or

R¹ is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₃₋₄ cycloalkyl; and R² is selected fromhalo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, andC₃₋₄ cycloalkyl;

R³ is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl, 6-10 membered aryl-C₁₋₆ alkyl, 4-10membered heterocycloalkyl-C₁₋₆ alkyl, and 5-10 membered heteroaryl-C₁₋₆alkyl; wherein said C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl, 6-10 membered aryl-C₁₋₆ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₆ alkyl, and 5-10 membered heteroaryl-C₁₋₆ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(3A) substituents;

R⁴ is selected from C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₄cycloalkyl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl,C₃₋₁₄ cycloalkyl-C₁₋₆ alkyl, 6-14 membered aryl-C₁₋₆ alkyl, 4-14membered heterocycloalkyl-C₁₋₆ alkyl, 5-14 membered heteroaryl-C₁₋₆alkyl, (R^(4A))_(o)-6-10 membered aryl-, and (R⁶)_(p)—C₁₋₆ alkyl-;wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₄cycloalkyl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl,C₃₋₁₄ cycloalkyl-C₁₋₆ alkyl, 6-14 membered aryl-C₁₋₆ alkyl, 4-14membered heterocycloalkyl-C₁₋₆ alkyl, and 5-14 membered heteroaryl-C₁₋₆alkyl are each optionally substituted by 1, 2, 3, 4, 5, or 6independently selected R^(4A) substituents;

each R⁵ is independently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 memberedaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a5), SR^(a5), NHOR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)NR^(c5)(OR^(a5)), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))R^(b5), NR^(c5)S(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)(═NR^(e5))R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),S(O)₂NR^(c5)R^(d5), OS(O)(═NR^(e5))R^(b5), OS(O)₂R^(b5),S(O)(═NR^(e5))R^(b5), SF₅, P(O)R^(f5)R^(g5), OP(O)(OR^(h5))(OR^(i5)),P(O)(OR^(h5))(OR^(i5)), and BR^(j5)R^(k5), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 memberedaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents;

each R⁶ is independently selected from CN, NO₂, OR^(a4), SR^(a4),NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)NR^(c4)(OR^(a4)),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))R^(b4),NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(d4), NR^(c4)S(O)₂R^(d4),NR^(c4)S(O)(═NR^(e4))R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4),OS(O)(═NR^(e4))R^(b4), OS(O)₂R^(b4), S(O)(═NR^(e4))R^(b4), SF₅,P(O)R^(f4)R^(g4), OP(O)(OR^(h4))(OR^(i4)), P(O)(OR^(h4))(OR^(i4)), andBR^(j4)R^(k4);

Ring moiety A is 4-14 membered heterocycloalkyl, wherein Ring moiety Ais attached to the —NH— group of Formula (I) at a ring member of asaturated or partially saturated ring of said 4-14 memberedheterocycloalkyl;

each R^(3A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a3), SR^(a3), NHOR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)NR^(c3)(OR^(a3)), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))R^(b3), NR^(c3)S(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)(═NR^(e3))R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),S(O)₂NR^(c3)R^(d3), OS(O)(═NR^(e3))R^(b3), OS(O)₂R^(b3),S(O)(═NR^(e3))R^(b3), SF₅, P(O)R^(f3)R^(g3), OP(O)(OR^(h3))(OR^(i3)),P(O)(OR^(h3))(OR^(i3)), and BR^(j3)R^(k3), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ halo alkyl, C₃₋₁₀ cycloalkyl, 6-10 memberedaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents;

each R^(4A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ halo alkyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a4), SR^(a4), NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)NR^(c4)(OR^(a4)), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))R^(b4), NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)(═NR^(e4))R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),S(O)₂NR^(c4)R^(d4), OS(O)(═NR^(e4))R^(b4), OS(O)₂R^(b4),S(O)(═NR^(e4))R^(b4), SF₅, P(O)R^(f4)R^(g4), OP(O)(OR^(h4))(OR^(i4)),P(O)(OR^(h4))(OR^(i4)), and BR^(j4)R^(k4), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 memberedaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents;

each R^(4B) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)NR^(c41)(OR^(a41)), C(O)OR^(a41), OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),C(═NR^(e41))R^(b41), C(═NR^(e41))NR^(c41)R^(d41),NR^(c41)C(═NR^(e41))NR^(c41)R^(d41), NR^(c41)C(═NR^(e41))R^(b41),NR^(c41)S(O)NR^(c41)R^(d41), NR^(c41)S(O)R^(b41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)(═NR^(e41))R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41),S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41), S(O)₂NR^(c41)R^(d41),OS(O)(═NR^(e41))R^(b41), OS(O)₂R^(b41), S(O)(═NR^(e41))R^(b41), SF₅,P(O)R^(f41)R^(g41), OP(O)(OR^(h41))(OR^(i41)), P(O)(OR^(h41))(OR^(i41)),and BR^(j4l)R^(k41), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(4C) substituents;

each R^(4C) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a42), SR^(a42), NHOR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42),C(O)NR^(c42)(OR^(a42)), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)NR^(c42)R^(d42),NR^(c42)C(O)R^(b42), NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42),C(═NR^(e42))R^(b42), C(═NR^(e42))NR^(c42)R^(d42),NR^(c42)C(═NR^(e42))NR^(c42)R^(d42), NR^(c42)C(═NR^(e42))R^(b42),NR^(c42)S(O)NR^(c42)R^(d42), NR^(c42)S(O)R^(b42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)(═NR^(e42))R^(b42), NR^(c42)S(O)₂NR^(c42)R^(d42),S(O)R^(b42), S(O)NR^(c42)R^(d42), S(O)₂R^(b42), S(O)₂NR^(c42)R^(d42),OS(O)(═NR^(e42))R^(b42), OS(O)₂R^(b42), S(O)(═NR^(e42))R^(b42), SF₅,P(O)R^(f42)R^(g42), OP(O)(OR^(h42))(OR^(i42)), P(O)(OR^(h42))(OR^(i42)),and BR^(j42)R^(k42), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(G) substituents;

each R^(5A) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-Cm alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl, OR^(a51),SR^(a51), NHOR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51),C(O)NR^(c51)(OR^(a51)), C(O)OR^(a51), OC(O)R^(b51),OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51), NR^(c51)NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),C(═NR^(e51))R^(b51), C(═NR^(e51))NR^(c51)R^(d51),NR^(c51)C(═NR^(e51))NR^(c51)R^(d51), NR^(c51)C(═NR^(e51))R^(b51),NR^(c51)S(O)NR^(c51)R^(d51), NR^(c51)S(O)R^(b51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)(═NR^(e51))R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51),S(O)R^(b51), S(O)NR^(c51)R^(d51), S(O)₂R^(b51), S(O)₂NR^(c51)R^(d51),OS(O)(═NR^(e51))R^(b51), OS(O)₂R^(b51), S(O)(═NR^(e51))R^(b51), SF₅,P(O)R^(f51)R^(g51), OP(O)(OR^(h51))(OR^(i51)), P(O)(OR^(h51))(OR^(i51)),and BR^(j5l)R^(k51), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-Cm alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(5B) substituents;

each R^(5B) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-Cm alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a52), SR^(a52), NHOR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)NR^(c52)(OR^(a52)), C(O)OR^(a52), OC(O)R^(b52),OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52), NR^(c52)NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), NR^(c52)C(O)OR^(a52), NR^(c52)C(O)NR^(c52)R^(d52),C(═NR^(e52))R^(b52), C(═NR^(e52))NR^(c52)R^(d52),NR^(c52)C(═NR^(e52))NR^(c52)R^(d52), NR^(c52)C(═NR^(e52))R^(b52),NR^(c52)S(O)NR^(c52)R^(d52), NR^(c52)S(O)R^(b52), NR^(c52)S(O)₂R^(b52),NR^(c52)S(O)(═NR^(e52))R^(b52), NR^(c52)S(O)₂NR^(c52)R^(d52),S(O)R^(b52), S(O)NR^(c52)R^(d52), S(O)₂R^(b52), S(O)₂NR^(c52)R^(d52),OS(O)(═NR^(e52))R^(b52), OS(O)₂R^(b52), S(O)(═NR^(e52))R^(b52), SF₅,P(O)R^(f52)R^(g52), OP(O)(OR^(h52))(OR^(i52)), P(O)(OR^(h52))(OR^(i52)),and BR^(j52)R^(k52), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(G) substituents;

each R^(a3), R^(c3), and R^(d3) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said Cue alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents;

or, any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 5- or 6-membered heteroaryl ora 4-10 membered heterocycloalkyl group, wherein the 5- or 6-memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(G)substituents;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(G) substituents;

each R^(e3) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl;

each R^(f3) and R^(g3) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered hetero cycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl;

each R^(h3) and R^(i3) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl;

each R^(j3) and R^(k3) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j3) and R^(k3) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-membered aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents;

or, any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 5- or 6-membered heteroaryl ora 4-10 membered heterocycloalkyl group, wherein the 5- or 6-memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4B)substituents;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents;

each R^(e4) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, Cue haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl;

each R^(f4) and R^(g4) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered hetero aryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl;

each R^(h4) and R^(i4) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl;

each R^(j4) and R^(k4) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j4) and R^(k4) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4C) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 5- or 6-memberedheteroaryl or a 4-14 membered heterocycloalkyl group, wherein the 5- or6-membered heteroaryl or 4-14 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(4C)substituents;

each R^(b41) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4C) substituents;

each R^(e41) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f41) and R^(g41) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h41) and R^(i41) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j41) and R^(k41) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j41) and R^(k41) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents;

or, any R^(c42) and R^(d42) attached to the same N atom, together withthe N atom to which they are attached, form a 5- or 6-memberedheteroaryl or a 4-14 membered heterocycloalkyl group, wherein the 5- or6-membered heteroaryl or 4-14 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents;

each R^(b42) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(G) substituents;

each R^(e42) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f42) and R^(g42) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(h42) and R^(i42) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j42) and R^(k42) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j42) and R^(k42) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cyclealkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents;

or, any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 5- or 6-membered heteroaryl ora 4-10 membered heterocycloalkyl group, wherein the 5- or 6-memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5A)substituents;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5A) substituents;

each R^(e5) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl;

each R^(f5) and R^(g5) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered hetero cycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl;

each R^(h5) and R^(i5) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-Cm alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;

each R^(j5) and R^(k5) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j5) and R^(k5) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

or, any R^(c51) and R^(d51) attached to the same N atom, together withthe N atom to which they are attached, form a 5- or 6-memberedheteroaryl or a 4-14 membered heterocycloalkyl group, wherein the 5- or6-membered heteroaryl or 4-14 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(5B)substituents;

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5B) substituents;

each R^(e51) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f51) and R^(g51) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(h51) and R^(i51) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j51) and R^(k51) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j51) and R^(k51) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents;

or, any R^(c52) and R^(d52) attached to the same N atom, together withthe N atom to which they are attached, form a 5- or 6-memberedheteroaryl or a 4-14 membered heterocycloalkyl group, wherein the 5- or6-membered heteroaryl or 4-14 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents;

each R^(b52) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(G) substituents;

each R^(e52) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f52) and R^(g52) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h52) and R^(i52) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j52) and R^(k52) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j52) and R^(k52) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;and

each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkyl carbonyl amino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments, R¹ is selected from H, halo, CN, and C₁₋₃haloalkyl; and

R² is selected from C₁₋₃ alkyl and C₁₋₃ haloalkyl; or R¹ is selectedfrom F, Cl, CN, and C₁₋₃ haloalkyl; and R² is selected from H, C₁₋₃alkyl, and C₁₋₃ haloalkyl.

In some embodiments, R¹ is selected from H, F, Cl, CN, and CF₃; and R²is selected from CH₃ and CF₃; or R¹ is selected from F, Cl, CN, and CF₃;and R² is selected from H, CH₃, and CF₃.

In some embodiments, R¹ is selected from Cl, CN, and CF₃; and R² is H.

In some embodiments, R¹ is selected from H, halo, C₁₋₄ alkyl, and C₁₋₄haloalkyl; and R² is selected from halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl;or R¹ is selected from halo, C₁₋₄ alkyl, and C₁₋₄ halo alkyl; and R² isselected from H, halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl.

In some embodiments, R¹ is selected from H and F; and R² is selectedfrom halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; or R¹ is selected from halo,C₁₋₄ alkyl, and CM haloalkyl; and R² is selected from H and F.

In some embodiments, R¹ is selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₃₋₄ cycloalkyl; and R² isselected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, and C₃₋₄ cycloalkyl.

In some embodiments, R¹ is selected from halo, CN, C₁₋₄ alkyl, and CMhaloalkyl; and R² is selected from H, halo, CN, C₁₋₄ alkyl, and C₁₋₄haloalkyl.

In some embodiments, R¹ is selected from H, F, Cl, CH₃, and CF₃; and R²is selected from F, Cl, CH₃, and CF₃; or R¹ is selected from F, Cl, CH₃,and CF₃; and R² is selected from H, F, Cl, CH₃, and CF₃.

In some embodiments, R¹ is selected from H and F; and R² is selectedfrom F, C₁, CH₃, and CF₃; or R¹ is selected from F, Cl, CH₃, and CF₃;and R² is selected from H and F.

In some embodiments, R¹ is selected from F, Cl, CH₃, and CF₃; and R² isselected from H, F, Cl, CH₃, and CF₃.

In some embodiments, R¹ is selected from F, Cl, CH₃, and CF₃; and R² isselected from H and F.

In some embodiments, R¹ is selected from H, D, halo, CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₃₋₄ cycloalkyl; and R²is selected from halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, and C₃₋₄ cycloalkyl.

In some embodiments, R¹ is selected from H, halo, C₁₋₄ alkyl, and CMhaloalkyl; and R² is selected from halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl.

In some embodiments, R¹ is selected from H, F, Cl, CH₃, and CF₃; and R²is selected from F, Cl, CH₃, and CF₃.

In some embodiments, R¹ is selected from H and F; and R² is selectedfrom F, C₁, CH₃, and CF₃.

In some embodiments, R³ is selected from H, D, halo, CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl; wherein said C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted by 1, 2, 3,or 4 independently selected R^(3A) substituents.

In some embodiments, R³ is selected from H, halo, CN, C₁₋₄ alkyl, andC₁₋₄ haloalkyl; wherein said C₁₋₄ alkyl and C₁₋₄ halo alkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(3A)substituents.

In some embodiments, R³ is selected from H, halo, CN, C₁₋₄ alkyl, andC₁₋₄ haloalkyl.

In some embodiments, R³ is selected from H and C₁₋₃ haloalkyl.

In some embodiments, R³ is selected from H, F, Cl, CN, methyl, ethyl,propyl, isopropyl, CF₃, CHF₂, CH₂F, CF₃CH₂, CHF₂CH₂, and CH₂FCH₂.

In some embodiments, R³ is selected from H, F, Cl, methyl, and CF₃.

In some embodiments, R³ is selected from H, CH₃, and CF₃.

In some embodiments, R³ is selected from H, Cl, CN and CF₃.

In some embodiments, R³ is selected from H, Cl, and CF₃.

In some embodiments, R³ is selected from H and CF₃.

In some embodiments:

each R^(3A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₄ cycloalkyl, OR^(a3),SR^(a3), NHOR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₄cycloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(G) substituents;

each R^(a3), R^(c3), and R^(d3) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and

each R^(b3) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, each R^(3A) is independently selected from halo,CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, OR^(a3), and NR^(c3)R^(d3); and eachR^(a3), R^(c3), and R^(d3) is independently selected from H, C₁₋₆ alkyl,and C₁₋₆ haloalkyl.

In some embodiments, R⁴ is selected from C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl, 6-10 memberedaryl-C₁₋₆ alkyl, 4-10 membered heterocycloalkyl-C₁₋₆ alkyl, 5-10membered heteroaryl-C₁₋₆ alkyl, (R^(4A))_(o)-6-10 membered aryl-, and(R⁶)_(p)—C₁₋₆ alkyl-; wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl, 6-10 memberedaryl-C₁₋₆ alkyl, 4-10 membered heterocycloalkyl-C₁₋₆ alkyl, and 5-10membered heteroaryl-C₁₋₆ alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(4A) substituents.

In some embodiments, R⁴ is selected from C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl, phenyl-C₁₋₆, alkyl, 4-7membered heterocycloalkyl-C₁₋₆ alkyl, 5-6 membered heteroaryl-Cue alkyl,(R^(4A))_(o)-phenyl-, and (R⁶)_(p)—C₁₋₆ alkyl-; wherein said C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,phenyl-C₁₋₆alkyl, 4-7 membered heterocycloalkyl-C₁₋₆ alkyl, and 5-6membered heteroaryl-C₁₋₆alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(4A) substituents.

In some embodiments, R⁴ is selected from C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-Cue alkyl, phenyl-C₁₋₆ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₆ alkyl, 5-6 membered heteroaryl-C₁₋₆ alkyl,(R^(4A))_(o)-phenyl-, and (R⁶)_(p)—C₁₋₆ alkyl-; wherein said C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₆ alkyl, and 5-6 membered heteroaryl-Cue alkyl areeach optionally substituted by 1, 2, or 3 independently selected R^(4A)substituents.

In some embodiments, R⁴ is selected from C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,4-7 membered heterocycloalkyl-C₁₋₆ alkyl, and (R⁶)_(p)—C₁₋₆ alkyl-;wherein said C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl, and 4-7 memberedheterocycloalkyl-Cue alkyl are each optionally substituted by 1, 2, 3,or 4 independently selected R^(4A) substituents.

In some embodiments, R⁴ is selected from C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,and 4-7 membered heterocycloalkyl-C₁₋₆ alkyl; wherein said C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₃₋₇cycloalkyl-C₁₋₆ alkyl, and 4-7 membered heterocycloalkyl-C₁₋₆ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(4A) substituents.

In some embodiments, R⁴ is selected from C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, (R^(4A))_(o)-phenyl-, and(R⁶)_(p)—C₁₋₆ alkyl-; wherein said C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, and4-7 membered heterocycloalkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(4A) substituents.

In some embodiments, R⁴ is selected from CF₃CH₂, cyclohexyl,tetrahydro-2H-pyranyl, N-methylpiperidin-4-yl, 2-fluorophenyl, and2-chlorophenyl.

In some embodiments, R⁴ is selected from C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, 5-6 membered hetero aryl, 4-7 membered heterocycloalkyl,C₃₋₇ cycloalkyl-Cue alkyl, 4-7 membered heterocycloalkyl-Cue alkyl,(R^(4A))_(o)-phenyl-, and (R⁶)_(p)—C₁₋₆ alkyl-; wherein said C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl, and 4-7 memberedheterocycloalkyl-C₁₋₆ alkyl are each optionally substituted by 1, 2, 3,or 4 independently selected R^(4A) substituents.

In some embodiments, R⁴ is selected from CF₃CH₂, CHF₂CH₂,—C(Me)₂-C(O)NH₂, cyclohexyl, tetrahydro-2H-pyranyl, cyclopropylmethyl,tetrahydrofuranylmethyl, piperidin-4-yl, pyridin-3-yl, pyridin-4-yl, andphenyl, wherein said cyclohexyl, pyridin-3-yl, pyridin-4-yl, and phenylare each substituted with 1 or 2 independently selected R^(4A)substituents.

In some embodiments:

each R^(4A) is independently selected from halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR³⁴, NR^(c4)R^(d4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(C4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), whereinsaid C₁₋₆ alkyl and C₁₋₆ haloalkyl is optionally substituted with 1 or 2independently selected R^(4B) substituents;

each R⁶ is independently selected from OR^(a4), NR^(c4)R^(d4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(C4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1 or 2 independently selected R^(4B)substituents;

each R^(4B) is independently selected from H, D, CN, OR^(a41),C(O)R^(b41), C(O)NR^(c41)R^(d41), C(O)OR^(a41), OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)C(O)R^(b41),NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41);

each R^(c41) and R^(d41) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-Cm alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C M alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4C) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, which is optionally substituted with 1 or 2independently selected R^(4C) substituents;

each R^(4C) is independently selected from H, D, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl, OR^(a42),C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42),NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)₂R^(b42), and S(O)₂NR^(c42)R^(d42),wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and C₃₋₆cycloalkyl-C₁₋₄ alkyl are each optionally substituted by 1 R^(G)substituent;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and

each R^(b42) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments:

each R^(4A) is independently selected from halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a4), and NR^(c4)R^(d4); wherein said C₁₋₆ alkyl isoptionally substituted with 1 or 2 independently selected R^(4B)substituents;

each R⁶ is independently selected from OR^(a4) and C(O)NR^(c4)R^(d4);

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆,alkyl, and C₃₋₇ cycloalkyl, wherein said C₁₋₆ alkyl and C₃₋₇ cycloalkylare each optionally substituted with 1 or 2 independently selectedR^(4B) substituents;

each R^(4B) is independently selected from H, D, and NR^(c41)R^(d41);

each R^(c41) and R^(d41) is independently selected from H, C₁₋₆ alkyl,C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl,C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl,and 5-6 membered heteroaryl-C₁₋₄ alkyl wherein said C₁₋₆ alkyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, or 3 independently selected R^(4C) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, which is optionally substituted with 1 or 2independently selected R^(4C) substituents;

each R^(4C) is independently selected from H, D, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl, OR^(a42),C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42),NR^(c42)C(O)OR^(a42), and S(O)₂R^(b42), wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₄ alkyl are each optionallysubstituted by 1 R^(G) substituent;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and

each R^(b42) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments:

each R^(4A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a4), SR^(a4), NHOR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein said Cue alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(4B) substituents;

each R⁶ is independently selected from CN, NO₂, OR^(a4), SR^(a4),NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(4B) is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a41), SR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41),NR^(c41)R^(d41), NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41),NR^(c41)C(O)NR^(c41)R^(d41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41),wherein said Cue alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4C) substituents;

each R^(4C) is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a42), SR^(a42), NHOR^(a42),C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42),NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)₂R^(b42), and S(O)₂NR^(c42)R^(d42);

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-Cm alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said Cue alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl. 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4C) substituents;

each R^(b41) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl and C₁₋₆haloalkyl; and

each R^(b42) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments:

each R^(4A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a4), SR^(a4), NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)₂R^(b4), andS(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents;

each R⁶ is independently selected from CN, NO₂, OR^(a4), SR^(a4),NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(C4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(4B) is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41),NR^(c41)R^(d41), NR^(c41)C(O)R^(b41), NR^(c41)S(O)₂R^(b41),S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41);

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and

each R^(b41) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments:

each R^(4A) is independently selected from halo, CN, NO₂, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(C4)S(O)₂R^(b4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₄ alkyl, C₁₋₄haloalkyl, and C₃₋₄ cycloalkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(4B) substituents;

each R⁶ is independently selected from CN, NO₂, OR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)S(O)₂R^(b4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(4B) is independently selected from H, halo, CN, C₁₋₆ alkyl, andC₁₋₆ haloalkyl;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl and C₁₋₆ haloalkylare each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents; and

each R^(b4) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, which are each optionally substituted with 1, 2, 3, or 4independently selected R^(4B) substituents.

In some embodiments, each R^(4A) is independently selected from halo,CN, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; and each R⁶ is halo, CN, OH, andC₁₋₄ alkoxy.

In some embodiments:

each R^(4A) is independently selected from halo, CN, NO₂, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(C4)S(O)₂R^(b4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₄ alkyl, C₁₋₄haloalkyl, and C₃₋₄ cycloalkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(4B) substituents;

each R⁶ is independently selected from CN, NO₂, OR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)S(O)₂R^(b4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(4B) is independently selected from CN, OH, C₁₋₃ alkyl, and C₁₋₃haloalkyl;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₄alkyl, C₁₋₄ haloalkyl, and C₃₋₄ cycloalkyl, wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, and C₃₋₄ cycloalkyl are each optionally substituted with1 or 2 independently selected R^(4B) substituents; and

each R^(b4) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, which are each optionally substituted with 1 or 2independently selected R^(4B) substituents.

In some embodiments:

each R^(4A) is independently selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, NH₂, and C(O)NHR^(d4);

each R⁶ is independently selected from CN, OH, C₁₋₄ alkoxy, andC(O)NHR^(d4);

each R^(d4) is independently selected from H, C₁₋₃ alkyl, and C₃₋₄cycloalkyl, wherein said C₃₋₄ cycloalkyl is optionally substituted withR^(4B); and

each R^(4B) is independently selected from CN, OH, C₁₋₄ alkyl, and CMhaloalkyl.

In some embodiments, Ring moiety A is a 4-10 membered heterocycloalkyl,wherein said heterocycloalkyl does not comprise an aromatic ring.

In some embodiments, Ring moiety A is monocyclic 4-7 memberedheterocycloalkyl.

In some embodiments, Ring moiety A is an azetidine ring, a pyrrolidinering, a piperidine ring, or an azepane ring.

In some embodiments, Ring moiety A is azetidin-3-yl, piperidin-3-yl, orpiperidin-4-yl.

In some embodiments, Ring moiety A is selected from:

wherein the nitrogen ring member is attached to —S(O)₂R^(b5).

In some embodiments, n is 1, 2, 3, or 4.

In some embodiments, n is 1, 2, or 3.

In some embodiments, n is 1 or 2.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, each R⁵ is independently selected from halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10membered heteroaryl-C₁₋₄ alkyl, OR^(a5), SR^(a5), NHOR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 memberedaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents.

In some embodiments, each R⁵ is independently selected from halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a5), SR^(a5), NHOR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents.

In some embodiments, each R⁵ is independently selected from halo, CN,NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)S(O)₂R^(b5), S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents.

In some embodiments, each R⁵ is independently selected from C₁₋₃ alkyland C₁₋₃ haloalkyl. In some embodiments, at least one R⁵ is S(O)₂R^(b5)(e.g., as in Formulas (II), (III), (IIIa), (IIIb) and (IIIc)).

In some embodiments, one R⁵ is S(O)₂R^(b5) (e.g., as in Formula (II),(III), (IIIa), (IIIb) or (IIIc)); and any remaining R⁵ are eachindependently selected C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₄ cycloalkyl, OR^(a5), C(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5).

In some embodiments, one R⁵ is S(O)₂R^(b5) (e.g., as in Formula (II),(III), (IIIa), (IIIb) or (IIIc)), wherein R^(b5) is selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1 or 2 independently selected R^(5A)substituents; and the remaining R⁵ are each independently selected fromCue alkyl, C₁₋₆ haloalkyl, and C₃₋₄ cycloalkyl.

In some embodiments, one R⁵ is S(O)₂R^(b5) (e.g., as in Formula (II),(III), (IIIa), (IIIb) or (IIIc)), wherein R^(b5) is selected from C₁₋₆alkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl,and phenyl-C₁₋₄ alkyl, which are each optionally substituted with 1 or 2independently selected R^(5A) substituents; and the remaining R⁵ areeach independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₄cycloalkyl.

In some embodiments, one R⁵ is S(O)₂R^(b5) (e.g., as in Formula (II),(III), (IIIa), (IIIb) or (IIIc)), wherein R^(b5) is selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-10 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1 or 2 independently selected R^(5A) substituents; and theremaining R⁵ are each independently selected from H, halo, and C₁₋₂alkyl.

In some embodiments, one R⁵ is S(O)₂R^(b5) (e.g., as in Formula (II),(III), (IIIa), (IIIb) or (IIIc)), wherein R^(b5) is selected from C₁₋₆alkyl, C₃₋₇ cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6membered heteroaryl, phenyl-C₁₋₄ alkyl, and 4-8 memberedheterocycloalkyl-C₁₋₄ alkyl, which are each optionally substituted with1 or 2 independently selected R^(5A) substituents; and the remaining R⁵are each independently selected from H, halo, and C₁₋₂ alkyl.

In some embodiments, one R⁵ is selected from S(O)₂R^(b5) (e.g., as inFormula (II), (III), (IIIa), (IIIb) or (IIIc)), wherein R^(b5) isselected from methyl, cyano-methyl, pyrazol-4-yl, N-methylpyrazol-4-yl,tetrahydro-2H-pyran-4-yl, benzyl, and phenyl, wherein said phenyl isoptionally substituted with CN or (morpholin-4-yl)-C(O)NH—; and theremaining R⁵ are each independently selected from C₁₋₆ alkyl.

In some embodiments, one R⁵ is selected from S(O)₂R^(b5) (e.g., as inFormula (II), (III), (IIIa), (IIIb) or (IIIc)), wherein R^(b5) isselected from methyl, cyano-methyl, pyrazol-4-yl, N-methylpyrazol-4-yl,tetrahydro-2H-pyran-4-yl, benzyl, pyridin-2-yl, 1-methyl-imidazol-4-yl,1-ethyl-imidazol-4-yl, and phenyl, wherein said phenyl is optionallysubstituted with CN or (morpholin-4-yl)-C(O)NH—; and the remaining R⁵are each independently selected from C₁₋₆ alkyl.

In some embodiments, each remaining R⁵ is independently selected from H,halo, C₁₋₂ alkyl, and C₁₋₂ haloalkyl.

In some embodiments, each remaining R⁵ is independently selected from H,halo, and C₁₋₂ alkyl.

In some embodiments, each remaining R⁵ is independently selected from H,F, and CH₃.

In some embodiments:

each R^(5A) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a51), SR^(a51), NHOR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51),C(O)OR^(a51), OC(O)R^(b51), OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),NR^(c51)S(O)₂R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(5B) substituents;

each R^(5B) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a52), SR^(a52), NHOR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)OR^(a52), OC(O)R^(b52), C(O)NR^(c52)R^(d52), NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), NR^(c52)C(O)OR^(a52), NR^(c52)C(O)NR^(c52)R^(d52),NR^(c52)S(O)₂R^(b52), NR^(c52)S(O)₂NR^(c52)R^(d52), S(O)R^(b52),S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52);

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-membered aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocyclo alkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C M alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5A) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5B) substituents;

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆, haloalkyl; and

each R^(b52) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments:

each R^(5A) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51), C(O)OR^(a51),OC(O)R^(b51), OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),NR^(c51)S(O)₂R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51), wherein said C₁₋₆ alkyl, C₁₋₆ halo alkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(5B) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(5B) substituents;

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,each of which is optionally substituted with 1, 2, or 3 independentlyselected R^(5B) substituents;

each R^(5B) is independently selected from H, halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, OR^(a52), NR^(c52)R^(d52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)OR^(a52), NHC(O)R^(b52), NHS(O)₂R^(b52), NHC(O)OR^(a52),NHC(O)NR^(c52)R^(d52), S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52);

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₄ alkyl, and C₁₋₄ haloalkyl; and

each R^(b52) is independently selected from C₁₋₄ alkyl and C₁₋₄haloalkyl.

In some embodiments:

each R^(5A) is independently selected from H, CN, C₁₋₃ alkyl, 4-7membered heterocycloalkyl, OR^(a51), NR^(c51)R^(d51), andNR^(c51)C(O)R^(b51), wherein said C₁₋₃ alkyl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, or 3independently selected R^(5B) substituents;

each R^(c51) and R^(d51) is independently selected from H, C₁₋₆ alkyl,and C₃₋₆ cycloalkyl;

each R^(b51) is independently selected from 4-7 memberedheterocycloalkyl;

each R^(5B) is independently selected from H and OR^(a52); and

each R^(a52) is independently selected from H and C₁₋₃ alkyl.

In some embodiments:

each R^(5A) is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ halo alkyl, C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a51), SR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51), C(O)OR^(a51),OC(O)R^(b51), OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),NR^(c51)S(O)₂R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ halo alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(5B) substituents;

each R^(5B) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₄ cycloalkyl, OR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)OR^(a52), OC(O)R^(b52), OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), NR^(c52)S(O)₂R^(b52), S(O)R^(b52), S(O)₂R^(b52),and S(O)₂NR^(c52)R^(d52);

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycle alkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedhetero aryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-Cm alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-Cm alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5A) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-Cm alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-Cm alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5B) substituents;

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and

each R^(b52) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments:

each R^(5A) is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₄ cycloalkyl, OR^(a51), C(O)R^(b51),C(O)NR^(c51)R^(d51), C(O)OR^(a51), OC(O)R^(b51), NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)S(O)₂R^(b51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₄cycloalkyl are each optionally substituted with 1 or 2 independentlyselected R^(5B) substituents;

each R^(5B) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OH, Cm alkoxy, Cm haloalkoxy, Cm alkylamino, and di(C₁₋₃alkyl)amino;

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C M alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1 or 2 independently selected R^(5A)substituents;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1 or 2 independently selectedR^(5A) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents; and

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5B) substituents.

In some embodiments:

n is 1, 2, 3, or 4;

o is 1 or 2;

p is 1 or 2;

R¹ is selected from H, halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; and R² isselected from halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; or

R¹ is selected from halo, C₁₋₄ alkyl, and C₁₋₄ halo alkyl; and R² isselected from H, halo, C₁₋₄ alkyl, and C₁₋₄ halo alkyl;

R³ is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ halo alkyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl; wherein said C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(3A) substituents;

each R^(3A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, OR^(a3), SR^(a3), NHOR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), whereinsaid C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₄ cycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(G)substituents;

each R^(a3), R^(c3), and R^(d3) is independently selected from H, C₁₋₄alkyl, and CM haloalkyl;

each R^(b3) is independently selected from C₁₋₄ alkyl and C₁₋₄haloalkyl;

R⁴ is selected from C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl, 6-10 membered aryl-C₁₋₆ alkyl, 4-10membered heterocycloalkyl-C₁₋₆ alkyl, 5-10 membered heteroaryl-C₁₋₆alkyl, (R^(4A))_(o)-6-10 membered aryl-, and (R⁶)_(p)—C₁₋₄ alkyl-;wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl, 6-10 membered aryl-C₁₋₆ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₆alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(4A) substituents;

each R^(4A) is independently selected from halo, CN, NO₂, C₁₋₄ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a4), SR^(a4), NHOR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₄ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ halo alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(4B) substituents;

each R⁶ is independently selected from CN, NO₂, OR^(a4), SR^(a4),NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(C4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(4B) is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41),NR^(c41)R^(d41), NR^(c41)C(O)R^(b41), NR^(c41)S(O)₂R^(b41),S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41);

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

each R^(b41) is independently selected from C₁ alkyl and C₁₋₆ haloalkyl;

Ring moiety A is monocyclic 4-7 membered heterocycloalkyl;

each R⁵ is independently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-Cm alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a5), SR^(a5), NHOR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-Cm alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(5A) substituents;

provided that at least one R⁵ is selected from S(O)₂R^(b5);

each R^(5A) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a51), SR^(a51), NHOR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51),C(O)OR^(a51), OC(O)R^(b51), OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),NR^(c51)S(O)₂R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(5B) substituents;

each R^(5B) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a52), SR^(a52), NHOR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)OR^(a52), OC(O)R^(b52), OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), NR^(c52)C(O)OR^(a52), NR^(c52)C(O)NR^(c52)R^(d52),NR^(c52)S(O)₂R^(b52), NR^(c52)S(O)₂NR^(c52)R^(d52), S(O)R^(b52),S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52);

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-membered aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocyclo alkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5A) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5B) substituents;

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and

each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-Cm alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, Cm alkoxy, C₁₋₃haloalkoxy, amino, Cm alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkyl carbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments:

n is 1, 2, or 3;

o is 1 or 2;

p is 1 or 2;

R¹ is selected from H, halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; and R² isselected from halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; or

R¹ is selected from halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; and R² isselected from H, halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl;

R³ is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₃₋₄ cycloalkyl; wherein said C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₃₋₄ cycloalkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(3A)substituents;

R^(3A) is independently selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, OR^(a3), and NR^(c3)R^(d3);

each R^(a3), R^(c3), and R^(d3) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

R⁴ is selected from C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl, 4-7 membered heterocycloalkyl-C₁₋₆ alkyl, 5-6membered heteroaryl-C₁₋₆ alkyl, (R^(4A))_(o)-phenyl-, and (R⁶)_(p)—C₁₋₆alkyl-; wherein said C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-Cue alkyl,phenyl-C₁₋₆ alkyl, 4-7 membered heterocycloalkyl-C₁₋₆ alkyl, and 5-6membered heteroaryl-C₁₋₆ alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(4A) substituents;

each R^(4A) is independently selected from halo, CN, NO₂, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(C4)S(O)₂R^(b4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₄ alkyl, C₁₋₄haloalkyl, and C₃₋₄ cycloalkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(4B) substituents;

each R⁶ is independently selected from CN, NO₂, OR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)S(O)₂R^(b4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(4B) is independently selected from H, halo, CN, C₁₋₆ alkyl, andC₁₋₆ haloalkyl;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl and C₁₋₆ haloalkylare each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents;

each R^(b4) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, which are each optionally substituted with 1, 2, 3, or 4independently selected R^(4B) substituents;

Ring moiety A is an azetidine ring, a pyrrolidine ring, a piperidinering, or an azepane ring;

one R⁵ is selected from S(O)₂R^(b5);

the remaining R⁵ are each independently selected C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₄ cycloalkyl, OR^(a5), C(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

each R^(5A) is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a51), SR^(a51), C(O)R^(b51),C(O)NR^(c51)R^(d51), C(O)OR^(a51), OC(O)R^(b51), OC(O)NR^(c51)R^(d51),NR^(c51)R^(d51), NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51),NR^(c51)C(O)NR^(c51)R^(d51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), and S(O)₂NR^(c51)R^(d51),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(5B) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₄ cycloalkyl, OR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)OR^(a52), OC(O)R^(b52), OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), NR^(c52)S(O)₂R^(b52), S(O)R^(b52), S(O)₂R^(b52),and S(O)₂NR^(c52)R^(d52);

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl. 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5A) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5B) substituents;

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and

each R^(b52) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments:

n is 1, 2, or 3;

o is 1 or 2;

p is 1 or 2;

R¹ is selected from H and F; and R² is selected from halo, C₁₋₄ alkyl,and C₁₋₄ haloalkyl; or

R¹ is selected from halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; and R² isselected from H and F.

R³ is selected from H, halo, CN, C₁₋₄ alkyl, and C₁₋₄ haloalkyl;

R⁴ is selected from C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, (R^(4A))_(o)-phenyl-, and (R⁶)_(p)—C₁₋₆ alkyl-;wherein said C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, and 4-7 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(4A) substituents;

each R^(4A) is independently selected from halo, CN, C₁₋₄ alkyl, andC₁₋₄ haloalkyl;

each R⁶ is CN, OH, and C₁₋₄ alkoxy;

Ring moiety A is azetidin-3-yl, piperidin-3-yl, or piperidin-4-yl;

one R⁵ is selected from S(O)₂R^(b5);

R^(b5) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1 or 2 independently selected R^(5A) substituents;

the remaining R⁵ are each independently selected from C₁₋₆ alkyl andC₁₋₆ haloalkyl;

each R^(5A) is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₄ cycloalkyl, OR^(a51), C(O)R^(b51),C(O)NR^(c51)R^(d51), C(O)OR^(a51), OC(O)R^(b51), NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)S(O)₂R^(b51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₂₋₄cycloalkyl are each optionally substituted with 1 or 2 independentlyselected R^(5B) substituents;

each R^(5B) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OH, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents; and

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5B) substituents.

In some embodiments:

n is 1, 2, or 3;

o is 1 or 2;

p is 1 or 2;

R¹ is selected from H, halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; and R² isselected from halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; or

R¹ is selected from halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; and R² isselected from H, halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl;

R³ is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₃₋₄ cycloalkyl; wherein said C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₃₋₄ cycloalkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(3A)substituents;

R^(3A) is independently selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, OR^(a3), and NR^(c3)R^(d3);

each R^(a3), R^(c3), and R^(d3) is independently selected from H, C₁₋₄alkyl, and CM haloalkyl;

R⁴ is selected from C₁₋₆ halo alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,phenyl-CM alkyl, 4-7 membered heterocycloalkyl-C₁₋₆ alkyl, 5-6 memberedheteroaryl-C₁₋₆ alkyl, (R^(4A))_(o)-phenyl-, and (R⁶)_(p)—C₁₋₆ alkyl-;wherein said C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₆ alkyl, 4-7 membered heterocycloalkyl-C₁₋₆ alkyl, and 5-6membered heteroaryl-C₁₋₆ alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(4A) substituents;

each R^(4A) is independently selected from halo, CN, NO₂, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(C4)S(O)₂R^(b4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₄ alkyl, C₁₋₄haloalkyl, and C₃₋₄ cycloalkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(4B) substituents;

each R⁶ is independently selected from CN, NO₂, OR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)S(O)₂R^(b4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₄alkyl, C₁₋₄ haloalkyl, and C₃₋₄ cycloalkyl, wherein said C₁₋₄ alkyl,C₁₋₄ haloalkyl, and C₃₋₄ cycloalkyl are each optionally substituted with1 or 2 independently selected R^(4B) substituents;

each R^(b4) is independently selected from C₁₋₄ alkyl and C₁₋₄haloalkyl, which are each optionally substituted with 1 or 2independently selected R^(4B) substituents;

each R^(4B) is independently selected from CN, OH, C₁₋₄ alkyl, and CMhaloalkyl;

Ring moiety A is an azetidine ring, a pyrrolidine ring, a piperidinering, or an azepane ring;

each R⁵ is independently selected C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₄cycloalkyl, OR^(a5), C(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

each R^(5A) is independently selected from H, halo, CN, NO₂, C₁₋₄ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a51), SR^(a51), C(O)R^(b51),C(O)NR^(c51)R^(d51), C(O)OR^(a51), OC(O)R^(b51), OC(O)NR^(c51)R^(d51),NR^(c51)R^(d51), NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51),NR^(c51)C(O)NR^(c51)R^(d51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), and S(O)₂NR^(c51)R^(d51),wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(5B) is independently selected from H, halo, CN, C₁₋₆ alkyl, Cuehaloalkyl, C₃₋₄ cycloalkyl, OR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)OR^(a52), OC(O)R^(b52), OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), NR^(c52)S(O)₂R^(b52), S(O)R^(b52), S(O)₂R^(b52),and S(O)₂NR^(c52)R^(d52);

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-Cm alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5A) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-Cm alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5B) substituents;

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and

each R^(b52) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments:

n is 1 or 2;

o is 1 or 2;

p is 1;

R¹ is selected from H and F; and R² is selected from halo, C₁₋₄ alkyl,and C₁₋₄ haloalkyl; or

R¹ is selected from halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; and R² isselected from H and F;

R³ is selected from H, halo, CN, C₁₋₄ alkyl, and C₁₋₄ haloalkyl;

R⁴ is selected from C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₃ alkyl,4-7 membered heterocycloalkyl-C₁₋₃ alkyl, (R^(4A))_(o)-phenyl-, and(R⁶)_(p)—C₁₋₆ alkyl-; wherein said C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, C₃₋₇ cycloalkyl-C₁₋₃alkyl, and 4-7 membered heterocycloalkyl-C₁₋₃ alkyl are each optionallysubstituted by 1 or 2 independently selected R^(4A) substituents;

each R^(4A) is independently selected from halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, NH₂, and C(O)NHR^(d4);

each R⁶ is independently selected from CN, OH, C₁₋₃ alkoxy, andC(O)NHR^(d4);

each R^(d4) is independently selected from H, C₁₋₄ alkyl, and C₃₋₄cycloalkyl, wherein said C₃₋₄ cycloalkyl is optionally substituted withR^(4B);

each R^(4B) is independently selected from CN, OH, C₁₋₄ alkyl, and CMhaloalkyl;

Ring moiety A is azetidin-3-yl, piperidin-3-yl, or piperidin-4-yl;

R^(b5) is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1 or 2 independently selected R^(5A) substituents;

the remaining R⁵ are each independently selected from C₁₋₆ alkyl andC₁₋₆ haloalkyl;

each R^(5A) is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₄ cycloalkyl, OR^(a51), C(O)R^(b51),C(O)NR^(c51)R^(d51), C(O)OR^(a51), OC(O)R^(b51), NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)S(O)₂R^(b51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₄cycloalkyl are each optionally substituted with 1 or 2 independentlyselected R^(5B) substituents;

each R^(5B) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OH, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(b51) is independently selected from Cm alkyl, Cm haloalkyl, Cmalkenyl, Cm alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-Cm alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5B) substituents.

In some embodiments:

n is 1 or 2;

o is 1 or 2;

p is 1 or 2;

R¹ is selected from H, halo, CN, and C₁₋₃ halo alkyl; and R² is selectedfrom halo, CN, C₁₋₃ alkyl, and C₁₋₃ haloalkyl; or

R¹ is selected from halo, CN, and C₁₋₃ haloalkyl; and R² is selectedfrom H, halo, CN, C₁₋₃ alkyl, and C₁₋₃ haloalkyl;

R³ is selected from H, halo, CN, C₁₋₃ alkyl, and C₁₋₃ haloalkyl;

R⁴ is selected from C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,phenyl-C₁₋₆, alkyl, 4-10 membered heterocycloalkyl-C₁₋₆ alkyl, 5-6membered heteroaryl-C₁₋₆ alkyl, (R^(4A))_(o)-phenyl-, and (R⁶)_(p)—C₁₋₆alkyl-; wherein said C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl, 4-10 membered heterocycloalkyl-C₁₋₆ alkyl, and 5-6membered heteroaryl-C₁₋₆ alkyl are each optionally substituted by 1, 2,or 3 independently selected R^(4A) substituents.

each R⁶ is independently selected from OR^(a4), SR^(a4), NHOR^(a4),NR^(c4)R^(d4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(4A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl,4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a4), SR^(a4), NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4B) substituents;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4B) substituents;

or, any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-10 membered heterocycloalkylgroup, which is optionally substituted with 1, 2, or 3 independentlyselected R^(4B) substituents;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-10 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, or 3 independently selected R^(4B) substituents;

each R^(4B) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),NR^(c41)S(O)₂R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)₂R^(b41), andS(O)₂NR^(c41)R^(d41), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, or 3 independently selected R^(4C) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said Cue alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4C) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, which is optionally substituted with 1 R^(4C)substituent;

each R^(b41) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, or 3 independently selected R^(4C) substituents;

each R^(4C) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a42), SR^(a42), NHOR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42),C(O)OR^(a42), OC(O)R^(b42), OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42),NR^(c42)C(O)R^(b42), NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42),NR^(c42)S(O)₂R^(b42), NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)₂R^(b42), andS(O)₂NR^(c42)R^(d42), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1R^(G) substituent;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C w alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1 R^(G) substituent;

or, any R^(c42) and R^(d42) attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, which is optionally substituted with 1 R^(G)substituent;

each R^(b42) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1 R^(G) substituent;

one R⁵ is S(O)₂R^(b5) (e.g., as in Formula (II), (III), (IIIa), (IIIb)or (IIIc)), wherein R^(b5) is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1 or 2 independently selectedR^(5A) substituents;

the remaining R⁵ are each independently selected from H, halo, and C₁₋₂alkyl;

each R^(5A) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51), C(O)OR^(a51),OC(O)R^(b51), OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),NR^(c51)S(O)₂R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(5B) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C w alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(5B) substituents;

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,each of which is optionally substituted with 1, 2, or 3 independentlyselected R^(5B) substituents;

each R^(5B) is independently selected from H, halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, OR^(a52), NR^(c52)R^(d52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)OR^(a52), NHC(O)R^(b52), NHS(O)₂R^(b52), NHC(O)OR^(a52),NHC(O)NR^(c52)R^(d52), S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52);

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₄ alkyl, and C₁₋₄ haloalkyl;

each R^(b52) is independently selected from C₁₋₄ alkyl and C₁₋₄haloalkyl; and

each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₄ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkyl carbonyl amino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkylaminocarbonylamino.

In some embodiments:

n is 1 or 2;

o is 1 or 2;

p is 1 or 2;

R¹ is selected from H, halo, CN, and C₁₋₄ haloalkyl; and R² is selectedfrom C₁₋₃ alkyl and C₁₋₃ haloalkyl; or

R¹ is selected from halo, CN, and C₁₋₃ haloalkyl; and R² is selectedfrom H, C₁₋₃ alkyl, and C₁₋₃ haloalkyl;

R³ is selected from H and C₁₋₃ haloalkyl;

R⁴ is selected from C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,phenyl-CM alkyl, 4-7 membered heterocycloalkyl-C₁₋₆ alkyl, 5-6 memberedheteroaryl-C₁₋₆ alkyl, (R^(4A))_(o)-phenyl-, and (R⁶)_(p)—C₁₋₆ alkyl-;wherein said C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl, 4-7 membered heterocycloalkyl-C₁₋₆ alkyl, and 5-6membered heteroaryl-C₁₋₆ alkyl are each optionally substituted by 1, 2,or 3 independently selected R^(4A) substituents.

each R^(4A) is independently selected from halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR³⁴, NR^(c4)R^(d4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(C4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), whereinsaid C₁₋₆ alkyl and C₁₋₆ haloalkyl is optionally substituted with 1 or 2independently selected R^(4B) substituents;

each R⁶ is independently selected from OR^(a4), NR^(c4)R^(d4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(C4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1 or 2 independently selected R^(4B)substituents;

each R^(4B) is independently selected from H, D, CN, OR^(a41),C(O)R^(b41), C(O)NR^(c41)R^(d41), C(O)OR^(a41), OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)C(O)R^(b41),NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41);

each R^(c41) and R^(d41) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4C) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, which is optionally substituted with 1 or 2independently selected R^(4C) substituents;

each R^(4C) is independently selected from H, D, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl, OR^(a42),C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42),NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)₂R^(b42), and S(O)₂NR^(c42)R^(d42),wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and C₃₋₆cycloalkyl-C₁₋₄ alkyl are each optionally substituted by 1 R^(G)substituent;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

each R^(b42) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

one R⁵ is S(O)₂R^(b5) (e.g., as in Formula (II), (III), (IIIa), (IIIb)or (IIIc)), wherein R^(b5) is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1 or 2 independently selectedR^(5A) substituents;

the remaining R⁵ are each independently selected from H, halo, and C₁₋₂alkyl;

each R^(5A) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51), C(O)OR^(a51),OC(O)R^(b51), OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),NR^(c51)S(O)₂R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(5B) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(5B) substituents;

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,each of which is optionally substituted with 1, 2, or 3 independentlyselected R^(5B) substituents;

each R^(5B) is independently selected from H, halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, OR^(a52), NR^(c52)R^(d52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)OR^(a52), NHC(O)R^(b52), NHS(O)₂R^(b52), NHC(O)OR^(a52),NHC(O)NR^(c52)R^(d52), S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52);

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₄ alkyl, and C₁₋₄ haloalkyl;

each R^(b52) is independently selected from C₁₋₄ alkyl and C₁₋₄haloalkyl; and

each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₄ alkylcarbonyloxy, C₁₋₃ alkyl carbonyl amino, C₁₋₄alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(CM alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments:

n is 1 or 2;

o is 1 or 2;

p is 1 or 2;

R¹ is selected from H, F, Cl, CN, and CF₃; and R² is selected from CH₃and CF₃; or

R¹ is selected from F, Cl, CN, and CF₃; and R² is selected from H, CH₃,and CF₃;

R³ is selected from H and C₁₋₃ halo alkyl;

R⁴ is selected from C₁₋₆ halo alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, (R^(4A))_(o)-phenyl-, and(R⁶)_(p)—C₁₋₆ alkyl-; wherein said C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl are each optionallysubstituted by 1, 2, or 3 independently selected R^(4A) substituents;

each R^(4A) is independently selected from halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a4), and NR^(c4)R^(d4); wherein said C₁₋₆ alkyl isoptionally substituted with 1 or 2 independently selected R^(4B)substituents;

each R⁶ is independently selected from OR^(a4) and C(O)NR^(c4)R^(d4);

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, and C₃₋₇ cycloalkyl, wherein said C₁₋₆ alkyl and C₃₋₇ cycloalkylare each optionally substituted with 1 or 2 independently selectedR^(4B) substituents;

each R^(4B) is independently selected from H, D, and NR^(c41)R^(d41);

each R^(c41) and R^(d41) is independently selected from H, C₁₋₆ alkyl,C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl,C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl,and 5-6 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₃₋₇cycloalkyl. 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, or 3 independently selected R^(4C) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, which is optionally substituted with 1 or 2independently selected R^(4C) substituents;

each R^(4C) is independently selected from H, D, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl, OR^(a42),C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42),NR^(c42)C(O)OR^(a42), and S(O)₂R^(b42), wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₄ alkyl are each optionallysubstituted by 1 R^(G) substituent;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

each R^(b42) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

one R⁵ is S(O)₂R^(b5) (e.g., as in Formula (II), (III), (IIIa), (IIIb)or (IIIc)), wherein R^(b5) is selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl,phenyl-Cm alkyl, and 4-8 membered heterocycloalkyl-C₁₋₄ alkyl, which areeach optionally substituted with 1 or 2 independently selected R^(5A)substituents;

the remaining R⁵ are each independently selected from H, halo, and C₁₋₂alkyl;

each R^(5A) is independently selected from H, CN, C₁₋₃ alkyl, 4-7membered heterocycloalkyl, OR^(a51), NR^(c51)R^(d51), andNR^(c51)C(O)R^(b51), wherein said C₁₋₃ alkyl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, or 3independently selected R^(5B) substituents;

each R^(c51) and R^(d51) is independently selected from H, C₁₋₆ alkyl,and C₃₋₆ cycloalkyl;

each R^(b51) is independently selected from 4-7 memberedheterocycloalkyl;

each R^(5B) is independently selected from H and OR^(a52);

each R^(a52) is independently selected from H and C₁₋₃ alkyl; and

each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkyl carbonyl amino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkylaminocarbonylamino.

In some embodiments, the compound is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein k is n−1, and theremaining variables are defined according to the definitions providedherein.

In some embodiments, the compound is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

k is n−1;

X is a bond or CH₂;

Y is a bond or CH₂; and

the remaining variables are defined according to the definitionsprovided herein.

In some embodiments, the compound is a compound of Formula (IIIa):

or a pharmaceutically acceptable salt thereof, wherein k is n−1, and theremaining variables are defined according to the definitions providedherein.

In some embodiments, the compound is a compound of Formula (IIIb):

or a pharmaceutically acceptable salt thereof, wherein k is n−1, and theremaining variables are defined according to the definitions providedherein.

In some embodiments, the compound is a compound of Formula (IIIc):

or a pharmaceutically acceptable salt thereof, wherein k is n−1, and theremaining variables are defined according to the definitions providedherein.

In some embodiments, the compound is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein k is 0-1; X¹ is Nor CH; R⁵ is H, F, or CH₃; R¹ is Cl, CF₃, or CN; R^(4A) is CN, CH₃, orhalo; R^(c41) and R^(d41) are each independently selected from H andC₁₋₄ alkyl; or R^(c41) and R^(d41), together with the N atom to whichthey are attached, form a 4-6 membered heterocycloalkyl ring, which isoptionally substituted by one C₁₋₃ alkyl group; and R^(4C) is H, C₁₋₃alkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl, or C(O)(C₁₋₄ alkyl). In someembodiments, R^(c41) is H; and R^(d41) is C₁₋₃ alkyl. In someembodiments, R^(c41) is H; and R^(d41) is CH₃. In some embodiments, or apharmaceutically acceptable salt thereof, wherein k is 0-1; R⁵ is H, F,or CH₃; R¹ is CF₃ or CN; R^(4A) is CN, CH₃, or halo; and R^(c41) andR^(d41) are each independently selected from H and C₁₋₃ alkyl; orR^(c41) and R^(d41), together with the N atom to which they areattached, form a 4-6 membered heterocycloalkyl ring, which is optionallysubstituted by one C₁₋₃ alkyl group.

In some embodiments, the compound is a compound of Formula (IVa):

or a pharmaceutically acceptable salt thereof, wherein k is 0-1; X¹ is Nor CH; R⁵ is H, F, or CH₃; R¹ is Cl, CF₃, or CN; R^(4A) is CN, CH₃ orhalo; R^(4C) is H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl, or C(O)(C₁₋₄alkyl). In some embodiments, k is 0-1; R⁵ is H, F, or CH₃; R¹ is CF₃ orCN; R^(4A) is CH₃ or halo; and R^(4C) is C₁₋₃ alkyl. In someembodiments, R^(4C) is CH₃. In some embodiments, R^(4C) is CH₃ orC(O)CH₃.

In some embodiments, the compound is a compound of Formula (IVb):

or a pharmaceutically acceptable salt thereof, wherein k is 0-1; R⁵ isH, F, or CH₃; R¹ is CF₃, CN, or C₁; R^(4A) is CH₃ or halo; and R^(4C) isC₁₋₃ alkyl. In some embodiments, R^(4C) is CH₃.

In some embodiments, the compound is a compound of Formula (V):

or a pharmaceutically acceptable salt thereof, wherein k is 0-1; R⁵ isH, F, or CH₃; R¹ is CF₃ or CN; and R^(a4) is H or C₁₋₃ alkyl. In someembodiments, R^(a4) is CH₃. In some embodiments, R^(a4) is H. In someembodiments, k is 0-1; R⁵ is H or F; R¹ is CF₃; and R^(a4) is CH₃. Insome embodiments, k is 0-1; R⁵ is H or F; R¹ is CF₃; and R^(a4) is H.

In some embodiments, the compound is a compound of Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein k is 0-1; R⁵ isH, F, or CH₃; and R¹ is CF₃ or CN. In some embodiments, k is 0; and R¹is CF₃. In some embodiments, k is 1; R⁵ is F; and R¹ is CF₃.

In some embodiments having any of the preceding Formulae, k is 0 or 1.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “phenyl”,“cycloalkyl”, “heterocycloalkyl”, or “heteroaryl” substituents or “—C₁₋₄alkyl-” and “alkylene” linking groups, as described herein, areoptionally replaced by deuterium atoms.

In some embodiments:

“4-8 membered heterocycloalkyl”, “4-10 membered heterocycloalkyl”, and“4-14 membered heterocycloalkyl” is azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, morpholinyl,dioxidothiomorpholino, tetrahydrofuranyl, tetrahydro-2H-pyranyl,2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, or7-oxa-4-azaspiro[2.5]octanyl; “4-7 membered heterocycloalkyl” isazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,morpholinyl, dioxidothiomorpholino, tetrahydrofuranyl,tetrahydro-2H-pyranyl, 2,5-diazabicyclo[2.2.1]heptanyl, or2-oxa-5-azabicyclo[2.2.1]heptanyl;

“C₃₋₇ cycloalkyl” or “C₃₋₁₀ cycloalkyl” is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl; and

“5-6 membered heteroaryl” and “4-10 membered heteroaryl” is pyrazolyl,imidazolyl, or pyridinyl.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

When an embodiment that recites “one R⁵ is S(O)₂R^(b5); and eachremaining R⁵ is independently selected from” is combined throughmultiple dependencies with a formula showing a floating —S(O)₂R^(b5)substituent (e.g., Formula (II)), then the floating —S(O)₂R^(b5)substituent on the formula replaces the “one R⁵ is S(O)₂R^(b5)” phrase.In the case of such an embodiment combined with Formula (II), one of R⁵substituents (of n possible R⁵ substituents) is replaced by theS(O)₂R^(b5) substituent on Formula (II), wherein each of the remainingR⁵ substituents (there being k remaining R⁵ substituents) isindependently selected from the “each remaining R⁵” list.

wherein k is n−1.

At various places in the present specification, divalent linkingsubstituents are described. Unless otherwise specified, it isspecifically intended that each divalent linking substituent includeboth the forward and backward forms of the linking substituent. Forexample, —NR(CR′R″)_(n)— includes both —NR(CR′R″)_(n)— and—(CR′R″)_(n)NR—. Where the structure clearly requires a linking group,the Markush variables listed for that group are understood to be linkinggroups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency, that the designated atom's normalvalency is not exceeded, and that the substitution results in a stablecompound.

As used herein, the term “independently selected from” means that eachoccurrence of a variable or substituent are independently selected ateach occurrence from the applicable list.

As used herein, the phrase “each ‘variable’ is independently selectedfrom” means substantially the same as wherein “at each occurrence‘variable’ is selected from.”

When any variable (e.g., R^(G)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 1, 2, 3, or 4 R^(G),then said group may optionally be substituted with up to four R^(G)groups and R^(G) at each occurrence is selected independently from thedefinition of R^(G). Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds;for example the combination of a first M group and second M group in thecombination of two R groups are permissible only if such combinations ofM-M result in stable compounds (e.g., M-M is not permissible if it willform highly reactive compounds such as peroxides having O—O bonds).

In some embodiments, when an optionally multiple substituent isdesignated in the form:

then it is to be understood that substituent R can occur p number oftimes on the ring, and R can be a different moiety at each occurrence.It is to be understood that each R group may replace any hydrogen atomattached to a ring atom, including one or both of the (CH₂)_(n) hydrogenatoms. Further, in the above example, should the variable Q be definedto include hydrogens, such as when Q is said to be CH₂, NH, etc., anyfloating substituent such as R in the above example, can replace ahydrogen of the Q variable as well as a hydrogen in any othernon-variable component of the ring.

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₃, CM. C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr), n-butyl,tert-butyl, isobutyl, sec-butyl: higher homologs such as2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl,and the like. In some embodiments, the alkyl group contains from 1 to 6carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, theterm “C_(n-m) alkoxy”, employed alone or in combination with otherterms, refers to a group of formula-O-alkyl, wherein the alkyl group hasn to m carbons. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., w-propoxy and isopropoxy), butoxy (e.g.,n-butoxy and tert-butoxy), and the like. In some embodiments, the alkylgroup has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2 fused rings). The term “C_(n-m)aryl” refers to an aryl group having from n to m ring carbon atoms. Arylgroups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl,indanyl, indenyl, and the like. In some embodiments, the aryl group has6 to 14 or 6 to 10 carbon atoms. In some embodiments, the aryl group isphenyl or naphthyl. In some embodiments, the aryl is phenyl.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments,halo is F, Cl, or Br. In some embodiments, halo is F or Cl. In someembodiments, halo is F. In some embodiments, halo is Cl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. Example haloalkoxy groupsinclude OCF₃ and OCHF₂. In some embodiments, the haloalkoxy group isfluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group of thehaloalkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkylgroups include CF₃, C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like.

As used herein, the term “C_(n-m) fluoroalkyl” refers to an alkyl grouphaving from one fluoro atom to 2s+1 fluoro atoms, where “s” is thenumber of carbon atoms in the alkyl group, wherein the alkyl group has nto m carbon atoms. In some embodiments, the alkyl group of the fluoroalkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Example fluoroalkylgroups include CF₃, C₂F₅, CHF₂, CH₂F, and the like.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkyl amino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group of the alkylamino has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group of the alkoxycarbonyl has 1 to 6, 1to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkyl carbonyl” refers to a group offormula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group of the alkylcarbonyl has 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group of the alkylcarbonylaminohas 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkoxycarbonylamino” refers to a groupof formula —NHC(O)O(C_(n-m) alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group of thealkoxycarbonylamino has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group of the alkylsulfonylaminohas 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group of the alkylaminosulfonylhas 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkylaminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group of thedialkylaminosulfonyl has, independently, 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group of thealkylaminosulfonylamino has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkylaminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup of the dialkylaminosulfonylamino has, independently, 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group of thealkylaminocarbonylamino has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkylaminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup of the dialkylaminocarbonylamino has, independently, 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group of the alkylcarbamyl has 1to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group of the alkylthio has 1 to 6, 1 to 4,or 1 to 3 carbon atoms. As used herein, the term “C_(n-m) alkylsulfinyl”refers to a group of formula —S(O)-alkyl, wherein the alkyl group has nto m carbon atoms. In some embodiments, the alkyl group of thealkylsulfinyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group of the alkylsulfonyl has 1 to 6, 1to 4, or 1 to 3 carbon atoms.

As used herein, the term “cyano-C_(n-m) alkyl” refers to a group offormula —(C_(n-m) alkylene)-CN, wherein the alkylene group has n to mcarbon atoms. As used herein, the term “cyano-C₁₋₆ alkyl” refers to agroup of formula —(C₁₋₆ alkylene)-CN. As used herein, the term“cyano-C₁₋₃ alkyl” refers to a group of formula —(C₁₋₄ alkylene)-CN.

As used herein, the term “HO—C_(n-m) alkyl” refers to a group of formula—(C_(n-m) alkylene)-OH, wherein the alkylene group has n to m carbonatoms. As used herein, the term “HO—C₁₋₃ alkyl” refers to a group offormula —(C₁₋₃ alkylene)-OH.

As used herein, the term “C_(n-m) alkoxy-C_(o-p) alkyl” refers to agroup of formula —(C_(n-m) alkylene)-O(C_(o-p) alkyl), wherein thealkylene group has n to m carbon atoms and the alkyl group has o to pcarbon atoms. As used herein, the term “Cue alkoxy-C₁₋₆ alkyl” refers toa group of formula —(C₁₋₆ alkylene)-O(C₁₋₆ alkyl). As used herein, theterm “C₁₋₃ alkoxy-C₁₋₃ alkyl” refers to a group of formula —(C₁₋₃alkylene)-O(C₁₋₃ alkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup of the dialkylamino independently has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup of the dialkylcarbamyl independently has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyloxy” is a group offormula —OC(O)-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group of the alkylcarbonyloxy has 1 to 6,1 to 4, or 1 to 3 carbon atoms.

As used herein, “aminocarbonyloxy” is a group of formula —OC(O)—NH₂.

As used herein, “C_(n-m) alkylaminocarbonyloxy” is a group of formula—OC(O)—NH-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group of the alkylaminocarbonyloxy has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “di(C_(n-m)alkyl)aminocarbonyloxy” is a group of formula—OC(O)—N(alkyl)₂, wherein each alkyl group has, independently, n to mcarbon atoms. In some embodiments, each alkyl group of thedialkylaminocarbonyloxy independently has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein “C_(n-m) alkoxycarbonylamino” refers to a group offormula —NHC(O)—O-alkyl, wherein the alkyl group has n to m carbonatoms.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups,spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group).Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo or thienyl derivatives of cyclopentane, cyclohexane,and the like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13 or 14 ring-forming carbons (i.e., C₃₋₁₄). In someembodiments, cycloalkyl is C₃₋₁₄ cycloalkyl, wherein 1, 2, 3, or 4ring-forming carbon atoms of said C₃₋₁₄ cycloalkyl can be optionallysubstituted by one or more oxo or sulfido. In some embodiments, thecycloalkyl is a C₃₋₁₀ monocyclic or bicyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₃₋₇ monocyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₄₋₇ monocyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₄₋₁₄ spirocycle or bridged cycloalkyl(e.g., a bridged bicycloalkyl group). Example cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbomyl, norpinyl, norcamyl, cubane, adamantane, bicyclo[1.1.1]pentyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl,bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g.,having 2, 3, or 4 fused rings) aromatic heterocycle having at least oneheteroatom ring member selected from N, O, S and B. In some embodiments,the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring membersindependently selected from N, O, S and B. In some embodiments, anyring-forming N in a heteroaryl moiety can be an N-oxide. In someembodiments, the heteroaryl is a 5-14 membered monocyclic or bicyclicheteroaryl having 1, 2, 3, or 4 heteroatom ring members independentlyselected from N, O, and S. In some embodiments, the heteroaryl is a 5-10membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4heteroatom ring members independently selected from N, O, and S. In someembodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2heteroatom ring members independently selected from N, O, S and B. Insome embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1or 2 heteroatom ring members independently selected from N, O, and S. Insome embodiments, the heteroaryl group contains 3 to 14, 3 to 10, 4 to14, 4 to 10, 3 to 7, or to 6 ring-forming atoms. In some embodiments,the heteroaryl group contains 5 to 14, 5 to 10, or 5 to 6 ring-formingatoms. In some embodiments, the heteroaryl group has 1 to 4 ring-formingheteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-formingheteroatoms or 1 ring-forming heteroatom. When the heteroaryl groupcontains more than one heteroatom ring member, the heteroatoms may bethe same or different. Example heteroaryl groups include, but are notlimited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, furyl, thienyl, triazolyl (e.g., 1,2,3-triazolyl,1,2,4-triazolyl, 1,3,4-triazolyl), tetrazolyl, thiadiazolyl (e.g.,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), quinolinyl,isoquinolinyl, indolyl, benzothienyl, benzofuranyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl, purinyl, triazinyl, thieno[3,2-b]pyridinyl,imidazo[1,2-a]pyridinyl, 1,5-naphthyridinyl,1H-pyrazolo[4.3-b]pyridinyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), 1,2-dihydro-1,2-azoborinyl, andthe like.

As used herein, “heterocycloalkyl” refers to monocyclic or polycyclicheterocycles having at least one non-aromatic ring (saturated orpartially unsaturated ring), wherein one or more of the ring-formingcarbon atoms of the heterocycloalkyl is replaced by a heteroatomselected from N, O, S, and B, and wherein the ring-forming carbon atomsand heteroatoms of the heterocycloalkyl group can be optionallysubstituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), orS(O)₂, etc.). Heterocycloalkyl groups include monocyclic and polycyclic(e.g., having 2 fused rings) systems. Included in heterocycloalkyl aremonocyclic and polycyclic 4-14, 4-12, 3-10-, 4-10-, 3-7-, 4-7-, and5-6-membered heterocycloalkyl groups. Heterocycloalkyl groups can alsoinclude spirocycles and bridged rings (e.g., a 5-14 membered bridgedbiheterocycloalkyl ring having one or more of the ring-forming carbonatoms replaced by a heteroatom independently selected from N, O, S, andB). The heterocycloalkyl group can be attached through a ring-formingcarbon atom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the non-aromatic heterocyclic ring, for example, benzo orthienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. In some embodiments, the heterocycloalkyl group contains3 to 14 ring-forming atoms, 4 to 14 ring-forming atoms, 3 to 10ring-forming atoms, 4 to ring-forming atoms, 3 to 7 ring-forming atoms,4 to 7 ring-forming atoms, 4 to 6 ring-forming atoms or 5 to 6ring-forming atoms. In some embodiments, the heterocycloalkyl group has1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1heteroatom.

In some embodiments, the hetero cycloalkyl is a 4-14 memberedmonocyclic, bicyclic, or tricyclic heterocycloalkyl having 1, 2, 3, or 4ring-forming hetero atoms independently selected from N, O, and S,wherein 1, 2, 3, or 4 ring-forming carbon or heteroatoms can beoptionally substituted by one or more oxo or sulfido. In someembodiments, the heterocycloalkyl is a 4-10 membered monocyclic,bicyclic, or tricyclic heterocycloalkyl having 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S,wherein 1, 2, 3, or 4 ring-forming carbon or heteroatoms can beoptionally substituted by one or more oxo or sulfido. In someembodiments, the heterocycloalkyl is a 4-7 membered monocyclicheterocycloalkyl having 1 or 2 ring-forming heteroatoms independentlyselected from N, O, and S, and wherein 1, 2 or 3 ring-forming carbon orheteroatoms can be optionally substituted by one or more oxo or sulfido.In some embodiments, the heterocycloalkyl is a monocyclic 4-6 memberedheterocycloalkyl having 1 or 2 heteroatoms independently selected fromN, O, S, and B and having one or more oxidized ring members.

Example heterocycloalkyl groups include pyrrolidin-2-one,1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl,morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, azepanyl, benzazapene, 1,2,3,4-tetrahydroisoquinoline,azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl,oxabicyclo[2.1.l]hexanyl, azabicyclo[2.2.1]heptanyl,diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl,diazabicyclo[3.1.l]heptanyl, azabicyclo[3.2.1]octanyl,diazabicyclo[3.2.l]octanyl, oxabicyclo[2.2.2]octanyl,azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl,oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl,oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl,azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl,azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxa-diazaspiro[4.4]nonanyl, and the like. Further heterocycloalkylgroups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl,tetrahydropyranyl, oxetanyl, azetidinyl, morpholino, thiomorpholino,dioxidothiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, azepanyl, benzazapene, 1,2,3,4-tetrahydroisoquinoline,azabicyclo[3.1.0]hexanyl, oxopiperazinyl, diazabicyclo[3.1.0]hexanyl,oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl,azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl,azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl,oxabicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl,diazaadamantanyl, oxa-adamantanyl, azaspiro[3.3]heptanyl,diazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl,azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, oxa-azaspiro[3.4]octanyl,oxa-azaspiro[2.5]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl,azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl,azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxa-diazaspiro[4.4]nonanyl, and the like.

As used herein, “C_(o-p) cycloalkyl-C_(n-m) alkyl-” refers to a group offormula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbonatoms and the alkylene linking group has n to m carbon atoms.

As used herein “C_(o-p) aryl-C_(n-m) alkyl-” refers to a group offormula aryl-alkylene-, wherein the aryl has o to p carbon ring membersand the alkylene linking group has n to m carbon atoms.

As used herein, “heteroaryl-C_(n-m) alkyl-” refers to a group of formulaheteroaryl-alkylene-, wherein alkylene linking group has n to m carbonatoms.

As used herein “heterocycloalkyl-C_(n-m) alkyl-” refers to a group offormula heterocycloalkyl-alkylene-, wherein alkylene linking group has nto m carbon atoms.

As used herein, the term “alkylene” refers a divalent straight chain orbranched alkyl linking group. Examples of “alkylene groups” includemethylene, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-dilyl,propan-1,2-diyl, propan-1,1-diyl and the like.

As used herein, the term “alkenylene” refers a divalent straight chainor branched alkenyl linking group. Examples of “alkenylene groups”include ethen-1,1-diyl, ethen-1,2-diyl, propen-1,3-diyl,2-buten-1,4-diyl, 3-penten-1,5-diyl, 3-hexen-1,6-diyl, 3-hexen-1,5-diyl,and the like.

As used herein, the term “alkynylene” refers a divalent straight chainor branched alkynyl linking group. Examples of “alkynylene groups”include propyn-1,3-diyl, 2-butyn-1,4-diyl, 3-pentyn-1,5-diyl,3-hexyn-1,6-diyl, 3-hexyn-1,5-diyl, and the like.

As used herein, an “alkyl linking group” is a bivalent straight chain orbranched alkyl linking group (“alkylene group”). For example, “C_(o-p)cycloalkyl-C_(n-m) alkyl-”, “C_(o-p) aryl-C_(n-m) alkyl-”,“phenyl-C_(n-m) alkyl-”, “heteroaryl-C_(n-m) alkyl-”, and“heterocycloalkyl-C_(n-m) alkyl-” contain alkyl linking groups. Examplesof “alkyl linking groups” or “alkylene groups” include methylene,ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-dilyl, propan-1,2-diyl,propan-1,1-diyl and the like.

As used herein, the term “oxo” refers to an oxygen atom (i.e., ═O) as adivalent substituent, forming a carbonyl group when attached to a carbon(e.g., C═O or C(O)), or attached to a nitrogen or sulfur heteroatomforming a nitroso, sulfinyl or sulfonyl group.

As used herein, the term “independently selected from” means that eachoccurrence of a variable or substituent are independently selected ateach occurrence from the applicable list.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration. The Formulas (e.g.,Formula (I), (II), etc.) provided herein include stereoisomers of thecompounds.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asP-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofa-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present disclosure include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present disclosure can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (ACN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in itsentirety.

Synthesis

As will be appreciated by those skilled in the art, the compoundsprovided herein, including salts and stereoisomers thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as thoseprovided in the Schemes below.

The reactions for preparing compounds described herein can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

The expressions, “ambient temperature” or “room temperature” or “r.t.”as used herein, are understood in the art, and refer generally to atemperature, e.g., a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TEC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) and normal phase silicachromatography.

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of formula (I) can be prepared by the general syntheticprocedure illustrated in Scheme 1. In Scheme 1,5-substituted-2,4-dichloropyrimidines of formula 1-1 react withappropriately substituted compounds of formula 1-2 (M=e.g.,appropriately functionalized boron species, i.e., boronic acid pinacolesters) by a suitable Suzuki cross-coupling (e.g., in the presence of apalladium catalyst, such as Pd(dppf)Cl₂ or Pd(PPh₃)₂Cl₂, and a base suchas sodium carbonate) in a suitable solvent (e.g., CH₃CN/H₂O,1,4-dioxane/H₂O) to provide compounds of formula 1-3. Appropriatelysubstituted compounds of formula 1-3 can then be converted intocompounds of formula (I) by a number of methods, e.g., by nucleophilicaromatic substitution with an appropriate amine nucleophile in asuitable solvent (e.g., DMSO, DMF, 1,4-dioxane) with or without asuitable base (e.g., triethylamine, N,N-diisopropylethylamine, orCs₂CO₃) or acid additive (e.g., a Lewis acid, such as ZnCl₂, or aBrønsted acid, such as p-toluenesulfonic acid), or by a suitable C—Ncross-coupling, including Buchwald-Hartwig animation (e.g., in thepresence of a palladium precatalyst, such as RuPhos Pd G3, and a basesuch as Cs₂CO₃) in a suitable solvent (e.g., 1,4-dioxane).

As shown in Scheme 2, the sequence of reactions can be modified for thelater stage exploration of substitution at positions R², R³, and R⁴. InScheme 2, compounds of formula 2-1 are accessed via the reaction ofappropriately substituted compounds of formula 1-1 with amines offormula 1-4 in the presence of zinc(II) chloride and triethylamine in asuitable solvent (e.g., a mixture of tert-butanol and1,2-dichloroethane). Suzuki cross-coupling (e.g., in the presence of apalladium catalyst, such as Pd(dppf)Cl₂ or Pd(PPh₃)₂C₁₋₂, and a basesuch as sodium carbonate) of appropriately substituted compounds offormula 2-1 with compounds of formula 1-2 (M=e.g., appropriatelyfunctionalized boron species, i.e., boronic acid pinacol esters)provides compounds of formula (I).

Compounds of formula (I) with a variety of substitution at position R⁴can be prepared using the processes illustrated in Scheme 3. In Scheme3, Suzuki cross-coupling of 4-chloropyrimidines of formula 2-1 withappropriately substituted pyrazoles of formula 3-1 (M=e.g.,appropriately functionalized boron species, i.e., boronic acid pinacolesters), where PG represents a protecting group (e.g., Boc or SEM),followed by protecting group removal provides compounds of formula 3-2.Under certain conditions, the protecting group may be removed during theSuzuki coupling to afford 1H-pyrazoles of formula 3-2 directly.Alternatively, various protecting group deprotection can be accomplishedunder standard conditions. Compounds of formula 3-2 can then beconverted into compounds of formula (I) by a variety of methods.Functionalization of the pyrazole nitrogen in appropriately substitutedcompounds of formula 3-2 may be achieved via reaction with R⁴-LG, whereLG represents a leaving group (e.g., halide, mesylate, or triflate),under basic conditions in a suitable solvent (e.g., DMF, THF). In turn,reaction of appropriately substituted compounds of formula 3-2 withalcohols of formula R⁴—OH under Mitsunobu conditions furnishes compoundsof formula (I). In cases where R⁴ is aryl, appropriately substitutedcompound of formula 3-2 can be converted into A-Aryl pyrazoles offormula (I) by a variety of methods, including nucleophilic aromaticsubstitution with an appropriate aryl halide under basic conditions(e.g., N,N-diisopropylethylamine, sodium hydride, or Cs₂CO₃) in asuitable solvent (e.g., DMSO, DMF, THF), or by a suitablecopper-mediated coupling, e.g., an Ullmann reaction with aryl halides(e.g., in the presence of a copper catalyst, such as copper(I) iodide, aligand, such as trans-N,N′-Dimethylcyclohexane-1,2-diamine,phenanthroline, or 2-hydroxybenzaldehyde oxime, and a base such asCs₂CO₃) in a suitable solvent (e.g., DMSO, DMF, CH₃CN), or a Chan-Lamcoupling with aryl boronic acids (e.g., in the presence of a coppercatalyst, such as copper(II) acetate, and pyridine) in a suitablesolvent (e.g., CH₂Cl₂). An array of functionality at position R⁴ offormula (I) can also be introduced by a nucleophilic conjugate additionreaction with various Michael-like acceptors (e.g., acrylates,acrylonitriles, or nitroalkenes) with or without a basic reactionadditive (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine) in asuitable solvent (e.g., CH₃CN, CH₂Cl₂).

As shown in Scheme 4, substituted pyrazoles of formula 1-2 (M=e.g.,appropriately functionalized boron species, i.e., boronic acid pinacolesters) can be prepared by a number of methods. Functionalization of thepyrazole nitrogen can be carried out by reaction of appropriatelysubstituted compounds of formula 4-1 with various electrophiles usingthe aforementioned methods described in Scheme 3. Halogenation (i.e.,iodination, bromination) of appropriately substituted pyrazole compoundsof formula 4-2 by treatment with a halogenating agent (e.g.,N-iodosuccinimide, bromine) in a suitable solvent (e.g., CF₃CN, AcOH)provides compounds of formula 4-3 (X=e.g., bromo, iodo). Finally,appropriately substituted compounds of formula 4-3 can be converted intocompounds of formula 1-2 by a variety of borylation reactions, includingtransmetalation (e.g., using an organolithium reagent, i.e., BuLi)followed by addition of a borylating reagent (e.g.,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in an aproticsolvent such as THF, or by palladium-catalyzed borylation (e.g., in thepresence of a palladium catalyst, such as Pd(dppf)Cl₂, a boron source,such as bis(pinacolato)diboron, and a base, such as potassium acetate)in a suitable solvent (e.g., 1,4-dioxane). Introduction of substitutionat R³ in compounds of formula 4-3 may be achieved by reaction ofappropriately substituted compounds of formula 4-4 (X=e.g., bromo, iodo)with a strong base (e.g., lithium diisopropylamide) and an appropriateelectrophile R³-LG (e.g., methyl iodide), where LG represents a leavinggroup (e.g., halide, mesylate, or triflate), in a suitable solvent(e.g., THF).

Methods of Use

Compounds of the present disclosure can inhibit CDK2 and therefore areuseful for treating diseases wherein the underlying pathology is, whollyor partially, mediated by CDK2. Such diseases include cancer and otherdiseases with proliferation disorder. In some embodiments, the presentdisclosure provides treatment of an individual or a patient in vivousing a compound of Formula (I) or a salt or stereoisomer thereof suchthat growth of cancerous tumors is inhibited. A compound of Formula (I)or of any of the formulas as described herein, or a compound as recitedin any of the claims and described herein, or a salt or stereoisomerthereof, can be used to inhibit the growth of cancerous tumors withaberrations that activate the CDK2 kinase activity. These include, butnot limited to, disease (e.g., cancers) that are characterized byamplification or overexpression of CCNE1 such as ovarian cancer, uterinecarcinosarcoma and breast cancer and p27 inactivation such as breastcancer and melanomas. Accordingly, in some embodiments of the methods,the patient has been previously determined to have an amplification ofthe cyclin E1 (CCNE1) gene and/or an expression level of CCNE1 in abiological sample obtained from the human subject that is higher than acontrol expression level of CCNE1. Alternatively, a compound of Formula(I) or of any of the formulas as described herein, or a compound asrecited in any of the claims and described herein, or a salt orstereoisomer thereof, can be used in conjunction with other agents orstandard cancer treatments, as described below. In one embodiment, thepresent disclosure provides a method for inhibiting growth of tumorcells in vitro. The method includes contacting the tumor cells in vitrowith a compound of Formula (I) or of any of the formulas as describedherein, or of a compound as recited in any of the claims and describedherein, or of a salt or stereoisomer thereof. In another embodiment, thepresent disclosure provides a method for inhibiting growth of tumorcells with CCNE1 amplification and overexpression in an individual or apatient. The method includes administering to the individual or patientin need thereof a therapeutically effective amount of a compound ofFormula (I) or of any of the formulas as described herein, or of acompound as recited in any of the claims and described herein, or a saltor a stereoisomer thereof.

In some embodiments, provided herein is a method of inhibiting CDK2,comprising contacting the CDK2 with a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. In some embodiments,provided herein is a method of inhibiting CDK2 in a patient, comprisingadministering to the patient a compound of Formula (I) or any of theformulas as described herein, a compound as recited in any of the claimsand described herein, or a salt thereof.

In some embodiments, provided herein is a method for treating cancer.The method includes administering to a patient (in need thereof), atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. In another embodiment,the cancer is characterized by amplification or overexpression of CCNE1.In some embodiments, the cancer is ovarian cancer or breast cancer,characterized by amplification or overexpression of CCNE1.

In some embodiments, provided herein is a method of treating a diseaseor disorder associated with CDK2 in a patient, comprising administeringto the patient a therapeutically effective amount of a compound ofFormula (I) or any of the formulas as described herein, a compound asrecited in any of the claims and described herein, or a salt thereof. Insome embodiments, the disease or disorder associated with CDK2 isassociated with an amplification of the cyclin E1 (CCNE1) gene and/oroverexpression of CCNE1.

In some embodiments, the disease or disorder associated with CDK2 isN-myc amplified neuroblastoma cells (see Molenaar, et al., Proc NatlAcad Sci USA 106(31): 12968-12973) K-Ras mutant lung cancers (see Hu,S., et al., Mol Cancer Ther, 2015. 14(11): p. 2576-85, and cancers withFBW7 mutation and CCNE1 overexpression (see Takada, et al., Cancer Res,2017. 77(18): p. 4881-4893).

In some embodiments, the disease or disorder associated with CDK2 islung squamous cell carcinoma, lung adenocarcinoma, pancreaticadenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma,ovarian serous cystadenocarcinoma, stomach adenocarcinoma, esophagealcarcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.

In some embodiments, the disease or disorder associated with CDK2 islung adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma,ovarian serous cystadenocarcinoma, or stomach adenocarcinoma.

In some embodiments, the disease or disorder associated with CDK2 is anadenocarcinoma, carcinoma, or cystadenocarcinoma.

In some embodiments, the disease or disorder associated with CDK2 isuterine cancer, ovarian cancer, stomach cancer, esophageal cancer, lungcancer, bladder cancer, pancreatic cancer, or breast cancer.

In some embodiments, the disease or disorder associated with CDK2 is acancer.

In some embodiments, the cancer is characterized by amplification oroverexpression of CCNE1. In some embodiments, the cancer is ovariancancer or breast cancer, characterized by amplification oroverexpression of CCNE1.

In some embodiments, the breast cancer is chemotherapy or radiotherapyresistant breast cancer, endocrine resistant breast cancer, trastuzumabresistant breast cancer, or breast cancer demonstrating primary oracquired resistance to CDK4/6 inhibition. In some embodiments, thebreast cancer is advanced or metastatic breast cancer.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers. The compounds of the present disclosureare also useful for the treatment of metastatic cancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma, BRAFand HSP90 inhibition-resistant melanoma), renal cancer (e.g., clear cellcarcinoma), prostate cancer (e.g., hormone refractory prostateadenocarcinoma), breast cancer, colon cancer, lung cancer (e.g.,non-small cell lung cancer and small cell lung cancer), squamous cellhead and neck cancer, urothelial cancer (e.g., bladder) and cancers withhigh microsatellite instability (MSI^(high)). Additionally, thedisclosure includes refractory or recurrent malignancies whose growthmay be inhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including follicularlymphoma, including relapsed or refractory NHL and recurrentfollicular), Hodgkin lymphoma or multiple myeloma) and combinations ofsaid cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to,cholangiocarcinoma, bile duct cancer, triple negative breast cancer,rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellularcarcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma,neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma,epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinalcancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinalcancer, islet cell cancer, oral cancer, mouth cancer, throat cancer,laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavitycancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer,renal cell carcinoma, salivary gland cancer, sinus cancer, spinalcancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteralcancer.

In some embodiments, the compounds of the present disclosure can be usedto treat sickle cell disease and sickle cell anemia.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), and essential thrombocytosis (ET)),myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma(T-ALL) and multiple myeloma (MM).

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer (SCLC), bronchogenic carcinoma, squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,medulloblastoma, glioma, ependymoma, germinoma (pinealoma),glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma,retinoblastoma, congenital tumors), and spinal cord (neurofibroma,meningioma, glioma, sarcoma), as well as neuroblastoma andLhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, Merkelcell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In someembodiments, diseases and indications that are treatable using thecompounds of the present disclosure include, but are not limited to,sickle cell disease (e.g., sickle cell anemia), triple-negative breastcancer (TNBC), myelodysplastic syndromes, testicular cancer, bile ductcancer, esophageal cancer, and urothelial carcinoma.

It is believed that compounds of Formula (I), or any of the embodimentsthereof, may possess satisfactory pharmacological profile and promisingbiopharmaceutical properties, such as toxicological profile, metabolismand pharmacokinetic properties, solubility, and permeability. It will beunderstood that determination of appropriate biopharmaceuticalproperties is within the knowledge of a person skilled in the art, e.g.,determination of cytotoxicity in cells or inhibition of certain targetsor channels to determine potential toxicity.

The terms “individual”, “patient,” and “subject” used interchangeably,refer to any animal, including mammals, preferably mice, rats, otherrodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates,and most preferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies I. Cancer Therapies

Cancer cell growth and survival can be impacted by dysfunction inmultiple signaling pathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well astargeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, and CDK4/6 kinase inhibitors suchas, for example, those described in WO 2006/056399 can be used incombination with the compounds of the present disclosure for treatmentof CDK2-associated diseases, disorders or conditions. Other agents suchas therapeutic antibodies can be used in combination with the compoundsof the present disclosure for treatment of CDK2-associated diseases,disorders or conditions. The one or more additional pharmaceuticalagents can be administered to a patient simultaneously or sequentially.

In some embodiments, the CDK2 inhibitor is administered or used incombination with a BCL2 inhibitor or a CDK4/6 inhibitor.

The compounds as disclosed herein can be used in combination with one ormore other enzyme/protein/receptor inhibitors therapies for thetreatment of diseases, such as cancer and other diseases or disordersdescribed herein. Examples of diseases and indications treatable withcombination therapies include those as described herein. Examples ofcancers include solid tumors and non-solid tumors, such as liquidtumors, blood cancers. Examples of infections include viral infections,bacterial infections, fungus infections or parasite infections. Forexample, the compounds of the present disclosure can be combined withone or more inhibitors of the following kinases for the treatment ofcancer: Akt1, Akt2, Akt3, BCL2, CDK4/6, TGF-βR, PKA, PKG, PKC,CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGER, HER2,HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha,beta, gamma, delta, and multiple or selective), CSF1R, KIT, FLK-II,KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron,Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR/Flt2,Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk,Fak, SYK, FRK, JAK, ABE, ALK and B-Raf. In some embodiments, thecompounds of the present disclosure can be combined with one or more ofthe following inhibitors for the treatment of cancer or infections.Non-limiting examples of inhibitors that can be combined with thecompounds of the present disclosure for treatment of cancer andinfections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g,pemigatinib (INCB54828), INCB62079), an EGER inhibitor (also known asErB-1 or HER-1; e.g., erlotinib, gefitinib, vandetanib, orsimertinib,cetuximab, necitumumab, or panitumumab), a VEGFR inhibitor or pathwayblocker (e.g. bevacizumab, pazopanib, sunitinib, sorafenib, axitinib,regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab,lenvatinib, ziv-aflibercept), a PARP inhibitor (e.g., olaparib,rucaparib, veliparib or niraparib), a JAK inhibitor (JAK1 and/or JAK2;e.g., ruxolitinib or baricitinib; or JAK1; e.g., itacitinib (INCB39110),INCB052793, or INCB054707), an IDO inhibitor (e.g., epacadostat, NLG919,or BMS-986205, MK7162), an LSD1 inhibitor (e.g., GSK2979552, INCB59872and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g.,parsaclisib (INCB50465) or INCB50797), a PI3K-gamma inhibitor such asPI3K-gamma selective inhibitor, a Pim inhibitor (e.g., INCB53914), aCSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer;e.g., INCB081776), an adenosine receptor antagonist (e.g., A2a/A2breceptor antagonist), an HPK1 inhibitor, a chemokine receptor inhibitor(e.g., CCR2 or CCR5 inhibitor), a SHP1/2 phosphatase inhibitor, ahistone deacetylase inhibitor (HDAC) such as an HDAC8 inhibitor, anangiogenesis inhibitor, an interleukin receptor inhibitor, bromo andextra terminal family members inhibitors (for example, bromodomaininhibitors or BET inhibitors such as INCB54329 and INCB57643), c-METinhibitors (e.g., capmatinib), an anti-CD19 antibody (e.g.,tafasitamab), an ALK2 inhibitor (e.g., INCB00928); or combinationsthereof.

In some embodiments, the compound or salt described herein isadministered with a PI3Kδ inhibitor. In some embodiments, the compoundor salt described herein is administered with a JAK inhibitor. In someembodiments, the compound or salt described herein is administered witha JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In someembodiments, the compound or salt described herein is administered witha JAK1 inhibitor. In some embodiments, the compound or salt describedherein is administered with a JAK1 inhibitor, which is selective overJAK2.

Example antibodies for use in combination therapy include, but are notlimited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g.,anti-VEGF-A), bevacizumab (AVASTIN™, e.g., anti-VEGF), panitumumab(e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), rituxan (e.g.,anti-CD20), and antibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present disclosure and are presented as a non-limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™(gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, intron, ara-C,adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine,ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine,6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™(oxaliplatin), pentostatine, vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase,teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,estramustine, medroxyprogesteroneacetate, leuprolide, flutamide,toremifene, goserelin, carboplatin, hydroxyurea, amsacrine,procarbazine, mitotane, mitoxantrone, levamisole, navelbene,anastrazole, letrazole, capecitabine, reloxafine, droloxafine,hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™(tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan),TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine,porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan,trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab,C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine,aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1,fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, andMDL-101,731.

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, bispecific ormulti-specific antibody, antibody drug conjugate, adoptive T celltransfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor, PI3Kδ inhibitor and the like. The compounds can beadministered in combination with one or more anti-cancer drugs, such asa chemotherapeutic agent. Examples of chemotherapeutics include any of:abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine,bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, busulfanintravenous, busulfan oral, calusterone, capecitabine, carboplatin,carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, andzoledronate.

Additional examples of chemotherapeutics include proteasome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™),nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceuticallyacceptable salts. Other example suitable Bcr-Abl inhibitors include thecompounds, and pharmaceutically acceptable salts thereof, of the generaand species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S.Ser. No. 60/578,491.

Example suitable Fit-3 inhibitors include midostaurin, lestaurtinib,linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib,crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and theirpharmaceutically acceptable salts. Other example suitable Fit-3inhibitors include compounds, and their pharmaceutically acceptablesalts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, andvemurafenib, and their pharmaceutically acceptable salts. Other examplesuitable RAF inhibitors include compounds, and their pharmaceuticallyacceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062,VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptablesalts. Other example suitable FAK inhibitors include compounds, andtheir pharmaceutically acceptable salts, as disclosed in WO 04/080980,WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO01/014402.

Example suitable CDK4/6 inhibitors include palbociclib, ribociclib,trilaciclib, lerociclib, and abemaciclib, and their pharmaceuticallyacceptable salts. Other example suitable CDK4/6 inhibitors includecompounds, and their pharmaceutically acceptable salts, as disclosed inWO 09/085185, WO 12/129344, WO 11/101409, WO 03/062236, WO 10/075074,and WO 12/061156.

In some embodiments, the compounds of the disclosure can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic in the treatment of cancer, and mayimprove the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfdzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). Additive or synergistic effects are desirableoutcomes of combining a CDK2 inhibitor of the present disclosure with anadditional agent.

The agents can be combined with the present compound in a single orcontinuous dosage form, or the agents can be administered simultaneouslyor sequentially as separate dosage forms.

The compounds of the present disclosure can be used in combination withone or more other inhibitors or one or more therapies for the treatmentof infections.

Examples of infections include viral infections, bacterial infections,fungus infections or parasite infections.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of thedisclosure where the dexamethasone is administered intermittently asopposed to continuously.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

In some further embodiments, combinations of the compounds of thedisclosure with other therapeutic agents can be administered to apatient prior to, during, and/or after a bone marrow transplant or stemcell transplant. The compounds of the present disclosure can be used incombination with bone marrow transplant for the treatment of a varietyof tumors of hematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self-antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses, echovirus, rhinovirus, coxsackie virus, comovirus, respiratory syncytialvirus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus,vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscumvirus, poliovirus, rabies virus, JC virus and arboviral encephalitisvirus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

II. Immune-Checkpoint Therapies

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors for the treatment of diseases, suchas cancer or infections. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CBL-B, CD20,CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3Kdelta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-IBB),ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TER (TLR7/8), TIGIT,CD112R, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, the immunecheckpoint molecule is a stimulatory checkpoint molecule selected fromCD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, theimmune checkpoint molecule is an inhibitory checkpoint molecule selectedfrom A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3,TIGIT, and VISTA. In some embodiments, the compounds provided herein canbe used in combination with one or more agents selected from KIRinhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4inhibitors and TGFR beta inhibitors.

In some embodiments, the compounds provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, GITR, and CD137 (also known as 4-1BB). In someembodiments, the inhibitor of an immune checkpoint molecule is anti-PD1antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 or PD-L1, e.g., an anti-PD-1 or anti-PD-L1monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1antibody is nivolumab, pembrolizumab, atezolizumab, durvalumab,avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab,spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001),camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224,AMP-514/MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736,FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316,CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333,MSB-2311, HLX20, TSR-042, or LY3300054. In some embodiments, theinhibitor of PD-1 or PD-L1 is one disclosed in U.S. Pat. Nos. 7,488,802,7,943,743, 8,008,449, 8,168,757, 8,217, 149, or 10,308,644; U.S. Publ.Nos. 2017/0145025, 2017/0174671, 2017/0174679, 2017/0320875,2017/0342060, 2017/0362253, 2018/0016260, 2018/0057486, 2018/0177784,2018/0177870, 2018/0179179, 2018/0179201, 2018/0179202, 2018/0273519,2019/0040082, 2019/0062345, 2019/0071439, 2019/0127467, 2019/0144439,2019/0202824, 2019/0225601, 2019/0300524, or 2019/0345170; or PCX Pub.Nos. WO 03042402, WO 2008156712, WO 2010089411, WO 2010036959, WO2011066342, WO 2011159877, WO 2011082400, or WO 2011161699, which areeach incorporated herein by reference in their entirety. In someembodiments, the inhibitor of PD-L1 is INCB086550.

In some embodiments, the antibody is an anti-PD-1 antibody, e.g., ananti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab,camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, AMP-224,JTX-4014, BOB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042.In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab,cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, orsintilimab. In some embodiments, the anti-PD-1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab.In some embodiments, the anti-PD-1 antibody is cemiplimab. In someembodiments, the anti-PD-1 antibody is spartalizumab. In someembodiments, the anti-PD-1 antibody is camrelizumab. In someembodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments,the anti-PD-1 antibody is toripalimab. In some embodiments, theanti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1antibody is AB122. In some embodiments, the anti-PD-1 antibody isAMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. Insome embodiments, the anti-PD-1 antibody is BGB-108. In someembodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, theanti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1antibody is LZM009. In some embodiments, the anti-PD-1 antibody isAK105. In some embodiments, the anti-PD-1 antibody is HLX10. In someembodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, theanti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In someembodiments, the anti-PD-1 monoclonal antibody is MGA012 (INCMGA0012;retifanlimab). In some embodiments, the anti-PD1 antibody is SHR-1210.Other anti-cancer agent(s) include antibody therapeutics such as 4-IBB(e.g., urelumab, utomilumab). In some embodiments, the inhibitor of animmune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonalantibody is atezolizumab, avelumab, durvalumab, tislelizumab,BMS-935559, MEDI4736, atezolizumab (MPDL3280A; also known as RG7446),avelumab (MSB0010718C), FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167,STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054. In someembodiments, the anti-PD-L1 antibody is atezolizumab, avelumab,durvalumab, or tislelizumab. In some embodiments, the anti-PD-L1antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibodyis avelumab. In some embodiments, the anti-PD-L1 antibody is durvalumab.In some embodiments, the anti-PD-L1 antibody is tislelizumab. In someembodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments,the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody isKN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In someembodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments,the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1antibody is A167. In some embodiments, the anti-PD-L1 antibody isSTI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. Insome embodiments, the anti-PD-L1 antibody is BGB-A333. In someembodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments,the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1antibody is LY3300054.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule that binds to PD-L1, or a pharmaceutically acceptablesalt thereof. In some embodiments, the inhibitor of an immune checkpointmolecule is a small molecule that binds to and internalizes PD-L1, or apharmaceutically acceptable salt thereof. In some embodiments, theinhibitor of an immune checkpoint molecule is a compound selected fromthose in US 2018/0179201, US 2018/0179197, US 2018/0179179, US2018/0179202, US 2018/0177784, US 2018/0177870, U.S. Ser. No. 16/369,654(filed Mar. 29, 2019), and U.S. Ser. No. 62/688,164, or apharmaceutically acceptable salt thereof, each of which is incorporatedherein by reference in its entirety.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4 and TGFR beta.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAGS, e.g., an anti-LAGS antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftilagimodalpha (IMP321).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isoleclumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT isOMP-31M32.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of VISTA. In some embodiments, the inhibitor of VISTA isJNJ-61610588 or CA-170.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 isenoblituzumab, MGD009, or 8H9.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR. In some embodiments, the inhibitor of KIR islirilumab or IPH4102.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of A2aR. In some embodiments, the inhibitor of A2aR isCPI-444.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-betais trabedersen, galusertinib, or M7824.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PI3K-gamma. In some embodiments, the inhibitor ofPI3K-gamma is IPI-549.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD47. In some embodiments, the inhibitor of CD47 isHu5F9-G4 or TTI-621.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isMEDI9447.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD70. In some embodiments, the inhibitor of CD70 iscusatuzumab or BMS-936561.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7/8, and CD137 (alsoknown as 4-1BB).

In some embodiments, the agonist of CD137 is urelumab. In someembodiments, the agonist of CD137 is utomilumab.

In some embodiments, the agonist of an immune checkpoint molecule is aninhibitor of GITR. In some embodiments, the agonist of GITR is TRX518,MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, orMEDI6469.In some embodiments, the agonist of an immune checkpointmolecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40Lfusion protein. In some embodiments, the anti-OX40 antibody isINCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998,BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein isMEDI6383.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD40. In some embodiments, the agonist of CD40 is CP-870893,ADC-1013, CDX-1140, SEA-CD40, R07009789, JNJ-64457107, APX-005M, or ChiLob 7/4.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of ICOS. In some embodiments, the agonist of ICOS isGSK-3359609, JTX-2011, or MEDI-570.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD28. In some embodiments, the agonist of CD28 istheralizumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of TLR7/8. In some embodiments, the agonist of TLR7/8 isMEDI9197.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor. In some embodiments, the bispecificantibody binds to PD-1 and PD-L1. In some embodiments, the bispecificantibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments,the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments,the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.Inhibitors of arginase inhibitors include INCB1158.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the disclosure can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral, or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the disclosure, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the disclosure may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the disclosure can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the disclosure can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the disclosure contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about to about 35, about35 to about 40, about 40 to about 45, or about 45 to about 50 mg of theactive ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the disclosure.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentdisclosure can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the disclosure. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the disclosure in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of thedisclosure can be provided in an aqueous physiological buffer solutioncontaining about 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the disclosure can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present disclosure relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating CDK2 in tissue samples,including human, and for identifying CDK2 activators by inhibitionbinding of a labeled compound. Substitution of one or more of the atomsof the compounds of the present disclosure can also be useful ingenerating differentiated ADME (Adsorption, Distribution, Metabolism andExcretion.) Accordingly, the present disclosure includes CDK2 assaysthat contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula (I) can be optionally substituted with deuterium atoms, suchas —CD₃ being substituted for —CH₃). In some embodiments, alkyl groupsof the disclosed Formulas (e.g., Formula (I)) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. For example, one or more hydrogen atoms in acompound presented herein can be replaced or substituted by deuterium(e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group can be replacedby deuterium atoms, such as —CD₃ being substituted for —CH₃). In someembodiments, the compound includes two or more deuterium atoms. In someembodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 deuteriumatoms. In some embodiments, all of the hydrogen atoms in a compound canbe replaced or substituted by deuterium atoms.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl,heterocycloalkyl, or heteroaryl substituents or —C₁₋₄ alkyl-, alkylene,alkenylene and alkynylene linking groups, as described herein, areoptionally replaced by deuterium atoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances, (seee.g., A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J.Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitutionat one or more metabolism sites may afford one or more of thetherapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro CDK2 labeling and competitionassays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵S canbe useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I,¹³¹I, ⁷⁵Br, ⁷⁶Br, or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S, and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the disclosure can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind activate CDK2 by monitoring itsconcentration variation when contacting with CDK2, through tracking ofthe labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known toinhibit CDK2 (i.e., standard compound). Accordingly, the ability of atest compound to compete with the standard compound for binding to CDK2directly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labeled and test compoundsare unlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, forexample, in the treatment or prevention of CDK2-associated diseases ordisorders (such as, e.g., cancer, an inflammatory disease, acardiovascular disease, or a neurodegenerative disease) which includeone or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thedisclosure. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

Biomarkers and Pharmacodynamics Markers

The disclosure further provides predictive markers (e.g., biomarkers andpharmacodynamic markers, e.g., gene copy number, gene sequence,expression levels, or phosphorylation levels) to identify those humansubjects having, suspected of having, or at risk of developing a diseaseor disorder associated with CDK2 for whom administering a CDK2 inhibitor(“a CDK2 inhibitor” as used herein refers to a compound of thedisclosure, or a pharmaceutically acceptable salt thereof) is likely tobe effective. The disclosure also provides pharmacodynamic markers(e.g., phosphorylation levels) to identify those human subjects having,suspected of having, or at risk of developing a disease or disorderassociated with CDK2 whom are responding to a CDK2 inhibitor.

The methods are based, at least in part, on the discovery that thefunctional status of cyclin dependent kinase inhibitor 2A (“CDKN2A”;also referred to as “p16”) is a biomarker for predicting sensitivity toCDK2-targeting therapies in G1/S-specific cyclin-E1-(“CCNE1-”) amplifiedcells suitable for use in patient stratification. In addition, thepresent invention is based, at least in part, on the discovery that, inCCNE1-amplified cell lines, the level of human retinoblastoma associatedprotein (“Rb”) phosphorylation at the serine corresponding to amino acidposition 780 of SEQ ID NO:3 is a pharmacodynamic marker for CDK2activity and is suitable for use in measuring CDK2 enzymatic activity incellular assay or preclinical and clinical applications, such as, e.g.,monitoring the progress of or responsiveness to treatment with a CDK2inhibitor.

CCNE1 and p16

CCNE1 and p16 have been identified in the Examples as genes, incombination, useful in predicting responsiveness (e.g., improvement indisease as evidenced by disease remission/resolution) of a subjecthaving a disease or disorder associated with CDK2 to a CDK2 inhibitor.

p16 (also known as cyclin-dependent kinase inhibitor 2A,cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, andp16-INK4a) acts as a negative regulator of the proliferation of normalcells by interacting with CDK4 and CDK6. p16 is encoded by the cyclindependent kinase inhibitor 2A (“CDKN2A”) gene (GenBank Accession No.NM_000077). The cytogenic location of the CDKN2A gene is 9p21.3, whichis the short (p) arm of chromosome 9 at position 21.3 The molecularlocation of the CDKN2A gene is base pairs 21,967,752 to 21,995,043 onchromosome 9 (Homo sapiens Annotation Release 109, GRCh38.p12). Geneticand epigenetic abnormalities in the gene encoding p16 are believed tolead to escape from senescence and cancer formation (Okamoto et al.,1994, PNAS 91 (23): 11045-9). Nonlimiting examples of geneticabnormalities in the gene encoding p16 are described in Table A, below.The amino acid sequence of human p16 is provided below (GenBankAccession No. NP_000068/UniProtKB Accession No. P42771):

(SEQ ID NO: 1)  1 MEPAAGSSME PSADWLATAA ARGRVEEVRA LLEAGALPNA PNSYGRRPIQ VMMMGSARVA 61 ELLLLHGAEP NCADPATLTR PVHDAAREGF LDTLVVLHRA GARLDVRDAW GRLPVDLAEE121 LGHRDVARYL RAAAGGTRGS NHARIDAAEG PSDIPD.

CCNE1 is a cell cycle factor essential for the control of the cell cycleat the G1/S transition (Ohtsubo et al., 1995, Mol. Cell. Biol.15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2, interactingwith CDK2 to form a serine/threonine kinase holoenzyme complex. TheCCNE1 subunit of this holoenzyme complex provides the substratespecificity of the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1is encoded by the cyclin E1 (“CCNE1”) gene (GenBank Accession No.NM_001238). The amino acid sequence of human CCNE1 is provided below(GenBank Accession No. NP_001229/UniProtKB Accession No. P24864):

(SEQ ID NO: 2)  1 mprerrerda kerdtmkedg gaefsarsrk rkanvtvflq dpdeemakid rtardqcgsq 61 pwdnnavcad pcsliptpdk edddrvypns tckpriiaps rgsplpvlsw anreevwkim121 lnkektylrd qhfleqhpll qpkmrailld wlmevcevyk lhretfylaq dffdrymatq181 envvktllql igisslfiaa kleeiyppkl hqfayvtdga csgdeiltme lmimkalkwr241 lspltivswl nvymqvayln dlhevllpqy pqqifiqiae lldlcvldvd clefpygila301 asalyhfsss elmqkvsgyq wcdiencvkw mvpfamvire tgssklkhfr gvadedahni361 qthrdsldll dkarakkaml seqnrasplp sglltppqsg kkgssgpema.

The Examples demonstrate CDK2-knockdown inhibits proliferation ofCCNE1-amplified cell lines, but not of CCNE1-non-amplified cell lines.Conversely, the Examples show that CDK4/6 inhibition inhibitsproliferation of CCNE1-non-amplified cell lines, but not ofCCNE1-amplified cell lines. The Examples further demonstrate thatpresence of a normal (e.g., non-mutated or non-deleted) p16 gene isrequired for the observed inhibition of cell proliferation inCCNE1-amplified cells treated with a CDK2-inhibitor. Accordingly, CCNE1and p16 are, together, a combination biomarker: cells that respond totreatment with a CDK2 inhibitor display an amplification of the CCNE1gene and/or an expression level of CCNE1 that is higher than a controlexpression level of CCNE1, and have a nucleotide sequence (e.g., a geneor an mRNA) that encodes the p16 protein (e.g., a p16 protein comprisingthe amino acid sequence of SEQ ID NO:1) and/or have p16 protein present,while control cells that do not respond to treatment with a CDK2inhibitor do not have an amplification of the CCNE1 gene and/or anexpression level of CCNE1 that is higher than a control expression levelof CCNE1, and tend to have a mutated or deleted gene that encodes thep16 protein and/or lack expression of p16 protein.

Thus, the disclosure provides a method of treating a human subjecthaving, suspected of having, or at risk of developing a disease ordisorder associated with CDK2, comprising administering to the humansubject a CDK2 inhibitor, wherein the human subject has been previouslydetermined to: (i) (a) have a nucleotide sequence encoding a p16 proteincomprising the amino acid sequence of SEQ ID NOT, (b) have a CDKN2A genelacking one or more inactivating nucleic acid substitutions and/ordeletions, and/or (c) express a p16 protein, and (ii) (a) have anamplification of the CCNE1 gene and/or (b) have an expression level ofCCNE1 in a biological sample obtained from the human subject that ishigher than a control expression level of CCNE1. In certain embodiments,the predictive methods described herein predict that the subject willrespond to treatment with the CDK2 inhibitor with at least 50%, at least60%, at least 70%, at least 80%, at least 90%, at least 95%, at least98% or 100% accuracy. For example, in some embodiments, if thepredictive methods described herein are applied to 10 subjects having,suspected of having, or at risk of developing a disease or disorderassociated with CDK2, and 8 of those 10 subjects are predicted torespond to treatment with a CDK2 inhibitor based on a predictive methoddescribed herein, and 7 of those 8 subjects do indeed respond totreatment with a CDK2 inhibitor, then the predictive method has anaccuracy of 87.5% (7 divided by 8). A subject is considered to respondto the CDK2 inhibitor if the subject shows any improvement in diseasestatus as evidenced by, e.g., reduction or alleviation in symptoms,disease remission/resolution, etc.

In some embodiments, the subject has a disease or disorder associatedwith CDK2. In some embodiments, the human subject has been previouslydetermined to: (i) (a) have a nucleotide sequence encoding a p16 proteincomprising the amino acid sequence of SEQ ID NO:1 and/or (b) a CDKN2Agene lacking one or more inactivating nucleic acid substitutions and/ordeletions, and (ii) have an amplification of the CCNE1 gene in abiological sample obtained from the human subject. In some embodiments,the CDKN2A gene encodes a protein comprising the amino acid sequence ofSEQ ID NO:1. In specific embodiments, the CDKN2A gene encodes a proteincomprising the amino acid sequence of SEQ ID NO:1.

In specific embodiments, the one or more inactivating nucleic acidsubstitutions and/or deletions in the CDKN2A gene is as described inTable A. In specific embodiments, the one or more inactivating nucleicacid substitutions and/or deletions in the CDKN2A gene is as describedin Yarbrough et al., Journal of the National Cancer Institute, 91(18):1569-1574, 1999; Liggett and Sidransky, Biology of Neoplasia, Journal ofOncology, 16(3): 1197-1206, 1998, and Cairns et al., Nature Genetics,11:210-212, 1995, each of which is incorporated by reference herein inits entirety.

TABLE A CDKN2A gene substitutions, deletions, and modificationsDescription Reference(s) C to T transition converting codon 232 of theRefSNP Accession No. rs121913388; CDKN2A gene from an arginine codon toa stop Kamb et al., Science 264: 436-440, codon 1994 19-basepairgermline deletion at nucleotide 225 RefSNP Accession No. rs587776716;causing a reading-frame shift predicted to Gruis et al., Nature Genet.10: 351- severely truncate p16 protein 353, 1995 6-basepair deletion atnucleotides 363-368 of the ClinVar Accession No. CDKN2A geneRCV000010017.2; Liu et al., Oncogene 11: 405-412, 1995 Mutation atchromosome 9: 21971058 predicted to RefSNP Accession No. rs104894094;substitute glycine corresponding to amino acid Ciotti et al., Am. J.Hum. Genet. 67: position 101 of SEQ ID NO: 1 with a tryptophan 311-319,2000 Germline mutation constituting an in-frame 3- ClinVar Accession No.basepair duplication at nucleotide 332 in exon 2 RCV000010020.3; Borg etal., Cancer of the CDKN2A gene Res. 56: 2497-2500, 1996 Mutationpredicted to substitute methionine RefSNP Accession No. rs104894095;corresponding to amino acid position 53 of SEQ Harland et al., Hum.Molec. Genet. 6: ID NO: 1 with an isoleucine 2061-2067, 1997 Mutationpredicted to substitute arginine RefSNP Accession No. rs104894097;corresponding to amino acid position 24 of SEQ Monzon et al., New Eng.J. Med. 338: ID NO: 1 with a proline 879-887, 1998 24-basepair repeatinserted at chromosome 9 RefSNP Accession No. rs587780668; between21974795 and 21974796 (forward Pollock et al., Hum. Mutat. 11: 424-strand) 431, 1998) G-to-T transversion at nucleotide-34 of the ClinVarAccession No. CDKN2A gene RCV000010024.5; Liu et al., Nature Genet. 21:128-132, 1999 Deletion of the p14(ARF)-specific exon 1-beta of ClinVarAccession No. CDKN2A RCV000010026.2; Randerson-Moor et al., Hum. Molec.Genet. 10: 55-62, 2001 Mutation predicted to substitute valine RefSNPAccession No. rs104894098; corresponding to amino acid position 126 ofSEQ Goldstein et al., Brit. J. Cancer 85: ID NO: 1 with an isoleucine527-530, 2001 Transition (IVS2-105 A-G) in intron 2 of the ClinVarAccession No. CDKN2A gene creating a false GT splice donorRCV000010028.3; Harland et al., site 105 bases 5-prime of exon 3resulting in Hum. Molec. Genet. 10: 2679-2686, aberrant splicing of themRNA 2001 Mutation predicted to result in substitution of RefSNPAccession No. rs113798404; glycine corresponding to amino acid position122 Hewitt et al., Hum. Molec. Genet. 11: of SEQ ID NO: 1 with anarginine 1273-1279, 2002 Mutation predicted to result in substitution ofRefSNP Accession No. rs113798404; valine corresponding to amino acidposition 59 of Yakobson et al., Melanoma Res. 11: SEQ ID NO: 1 with anarginine 569-570, 2001 Tandem germline339G-C transversion and a RefSNPAccession Nos. rs113798404 340C-T transition in the CDKN2A generesulting and rs104894104; Kannengiesser et in substitution of prolinecorresponding to amino al., Genes Chromosomes Cancer 46: acid position114 of SEQ ID NO: 1 with a serine 751-760, 2007 Mutation predicted toresult in substitution of RefSNP Accession No. rs104894109; serinecorresponding to amino acid position 56 of Kannengiesser et al., GenesSEQ ID NO: 1 with an isoleucine Chromosomes Cancer 46: 751-760, 2007Mutation predicted to result in substitution of RefSNP Accession No.rs137854599; glycine corresponding to amino acid position 89 Goldsteinet al., J. Med. Genet. 45: of SEQ ID NO: 1 with an aspartic acid284-289, 2008 Heterozygous A-to-G transition in exon 1B of the ClinVarAccession no. CDKN2A gene, affecting splicing of the RCV000022943.3;Binni et al., Clin. p14(ARF) isoform Genet. 77: 581-586, 2010Heterozygous 5-bp duplication (19_23dup) in the ClinVar Accession No.CDKN2A gene, resulting in a frameshift and RCV000030680.6; Harinck, F.,Kluijt premature termination et al., J. Med. Genet. 49: 362-365, 2012Mutation predicted to result in substitution of Yarbrough et al.,Journal of the aspartic acid corresponding to amino acid National CancerInstitute, position 84 of SEQ ID NO: 1 with a valine 91(18): 1569-1574Mutation predicted to result in substitution of Yarbrough et al.,Journal of the aspartic acid corresponding to amino acid National CancerInstitute, position 84 of SEQ ID NO: 1 with a glycine 91(18): 1569-1574Mutation predicted to result in substitution of Yarbrough et al.,Journal of the arginine corresponding to amino acid position 87 NationalCancer Institute, of SEQ ID NO: 1 with a proline 91(18): 1569-1574Mutation predicted to result in substitution of Yarbrough et al.,Journal of the proline corresponding to amino acid position 48 NationalCancer Institute, of SEQ ID NO: 1 with a leucine 91(18): 1569-1574Mutation predicted to result in substitution of Yarbrough et al.,Journal of the aspartic acid corresponding to amino acid National CancerInstitute, position 74 of SEQ ID NO: 1 with a asparagine 91(18):1569-1574 Mutation predicted to result in substitution of Yarbrough etal., Journal of the arginine corresponding to amino acid position 87National Cancer Institute, of SEQ ID NO: 1 with a leucine 91(18):1569-1574 Mutation predicted to result in substitution of Yarbrough etal., Journal of the asparagine corresponding to amino acid positionNational Cancer Institute, 71 of SEQ ID NO: 1 with a serine 91(18):1569-1574 Mutation predicted to result in substitution of Yarbrough etal., Journal of the arginine corresponding to amino acid position 80National Cancer Institute, of SEQ ID NO: 1 with a leucine 91(18):1569-1574 Mutation predicted to result in substitution of Yarbrough etal., Journal of the histidine corresponding to amino acid position 83National Cancer Institute, of SEQ ID NO: 1 with a tyrosine 91(18):1569-1574

The disclosure also features a method of treating a human subjecthaving, suspected of having, or at risk of developing a disease ordisorder associated with CDK2, comprising: (i) identifying, in abiological sample obtained from the human subject: (a) a nucleotidesequence encoding a p16 protein comprising the amino acid sequence ofSEQ ID NO:1, (b) a CDKN2A gene lacking one or more inactivating nucleicacid substitutions, and/or (c) the presence of a p16 protein; (ii)identifying, in a biological sample obtained from the human subject: (a)an amplification of the CCNE1 gene and/or (b) an expression level ofCCNE1 that is higher than a control expression level of CCNE1; and (iii)administering a CDK2 inhibitor to the human subject. In someembodiments, the subject has a disease or disorder associated with CDK2.In some embodiments, the subject is suspected of having or is at risk ofdeveloping a disease or disorder associated with CDK2. In someembodiments, the method comprises: (i) identifying, in a biologicalsample obtained from the human subject: (a) a nucleotide sequenceencoding a p16 protein comprising the amino acid sequence of SEQ ID NOT,(b) a CDKN2A gene lacking one or more inactivating nucleic acidsubstitutions and/or deletions, and/or (c) the presence of a p16protein; (ii) identifying, in a biological sample obtained from thehuman subject: (a) an amplification of the CCNE1 gene; and (iii)administering a CDK2 inhibitor to the human subject.

The disclosure also features a method of predicting the response of ahuman subject having, suspected of having, or at risk of developing adisease or disorder associated with CDK2 to a CDK2 inhibitor,comprising: (i) determining, from a biological sample obtained from thehuman subject: (a) the nucleotide sequence of a CDKN2A gene, (b) thepresence of a CDKN2A gene lacking one or more inactivating nucleic acidsubstitutions and/or deletions, and/or (c) the presence of a p16protein; and (ii) determining, from a biological sample obtained fromthe human subject: (a) the copy number of the CCNE1 gene and/or (b) theexpression level of CCNE1, wherein (1) (a) the presence of a CDKN2A geneencoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, (b) the presence of a CDKN2A gene lacking one or more inactivatingnucleic acid substitutions and/or deletions, and/or (c) the presence ofa p16 protein, and (2) (a) an amplification of the CCNE1 gene and/or (b)an expression level of CCNE1 that is higher than a control expressionlevel of CCNE1, is predictive that the human subject will respond to theCDK2 inhibitor. In some embodiments, the subject has a disease ordisorder associated with CDK2. In some embodiments, the subject issuspected of having or is at risk of developing a disease or disorderassociated with CDK2. In some embodiments, the method comprises: (i)determining, from a biological sample obtained from the human subject:(a) the nucleotide sequence of a CDKN2A gene and/or (b) the presence ofa CDKN2A gene lacking one or more inactivating nucleic acidsubstitutions and/or deletions; and (ii) determining, from a biologicalsample obtained from the human subject: (a) the copy number of the CCNE1gene, wherein (1) (a) the presence of a CDKN2A gene encoding a p16protein comprising the amino acid sequence of SEQ ID NO: 1 and/or (b)the presence of a CDKN2A gene lacking one or more inactivating nucleicacid substitutions and/or deletions, and (2) (a) an amplification of theCCNE1 gene, is predictive that the human subject will respond to theCDK2 inhibitor.

In specific embodiments, the (i) determining of (a) the nucleotidesequence of a CDKN2A gene, (b) the presence of a CDKN2A gene lacking oneor more inactivating nucleic acid substitutions and/or deletions, and/or(c) the presence of a p16 protein is performed before (e.g., at least 1day, at least 2 days, at least 3 days, at least 4 days, at least 5 days,at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, orat least 4 weeks, or from 6 hours to 16 hours, from 6 hours to 20 hours,or from 6 hours to 24 hours, from 2 days to 3 days, from 2 days to 4days, from 2 days to 5 days, from 2 days to 6 days, from 2 days to 7days, from 1 week to 2 weeks, from 1 week to 3 weeks, or from 1 week to4 weeks before) administering to the human subject the CDK2 inhibitor.In specific embodiments, the (ii) determining of (a) the copy number ofthe CCNE1 gene and/or (b) the expression level of CCNE1 in thebiological sample obtained from the human subject is performed before(e.g., at least 1 day, at least 2 days, at least 3 days, at least 4days, at least 5 days, at least 6 days, at least 7 days, at least 2weeks, at least 3 weeks, or at least 4 weeks, or from 6 hours to 16hours, from 6 hours to 20 hours, or from 6 hours to 24 hours, from 2days to 3 days, from 2 days to 4 days, from 2 days to 5 days, from 2days to 6 days, from 2 days to 7 days, from 1 week to 2 weeks, from 1week to 3 weeks, or from 1 week to 4 weeks before) administering to thehuman subject the CDK2 inhibitor.

An amplification of the CCNE1 gene and/or an expression level of CCNE1that is higher than a control expression level of CCNE1, combined withthe presence of a CDKN2A gene encoding a p16 protein comprising theamino acid sequence of SEQ ID NO:1, the presence of a CDKN2A genelacking one or more inactivating nucleic acid substitutions and/ordeletions, and/or the presence of a p16 protein (e.g., a p16 proteincomprising the amino acid sequence of SEQ ID NO: 1), isindicative/predictive that a human subject having, suspected of having,or at risk of developing a disease or disorder associated with CDK2 willrespond to a CDK2 inhibitor.

In some embodiments, the CCNE1 gene is amplified to a gene copy numberfrom 3 to 25. In specific embodiments, the CCNE1 gene is amplified to agene copy number of at least 3. In specific embodiments, the CCNE1 geneis amplified to a gene copy number of at least 5. In specificembodiments, the CCNE1 gene is amplified to a gene copy number of atleast 7. In specific embodiments, the CCNE1 gene is amplified to a genecopy number of at least 10. In specific embodiments, the CCNE1 gene isamplified to a gene copy number of at least 12. In specific embodiments,the CCNE1 gene is amplified to a gene copy number of at least 14. Inspecific embodiments, the CCNE1 gene is amplified to a gene copy numberof at least 21.

In specific embodiments, the expression level of CCNE1 is the level ofCCNE1 mRNA. In specific embodiments, the expression level of CCNE1 isthe level of CCNE1 protein.

In some embodiments of the foregoing methods, the control expressionlevel of CCNE1 is a pre-established cut-off value. In some embodimentsof the foregoing methods, the control expression level of CCNE1 is theexpression level of CCNE1 in a sample or samples obtained from one ormore subjects that have not responded to treatment with the CDK2inhibitor.

In some embodiments of the foregoing methods, the expression level ofCCNE1 is the expression level of CCNE1 mRNA. In some embodiments of theforegoing methods, the expression level of CCNE1 is the expression levelof CCNE1 protein. In some embodiments in which the expression level ofCCNE1 is the expression level of CCNE1 mRNA, the expression level ofCCNE1 is measured by RNA sequencing, quantitative polymerase chainreaction (PCR), in situ hybridization, nucleic acid array or RNAsequencing. In some embodiments in which the expression level of CCNE1is the expression level of CCNE1 protein, the expression level of CCNE1is measured by western blot, enzyme-linked immunosorbent assay, orimmunohistochemistry staining.

Rb S780

The disclosure also features a method for assessing the CDKN2A gene andthe CCNE1 gene, comprising determining, from a biological sample orbiological samples obtained from a human subject having a disease ordisorder associated with CDK2, (i) (a) the nucleotide sequence of aCDKN2A gene or (b) the presence of a CDKN2A gene lacking one or moreinactivating nucleic acid substitutions and/or deletions, and (ii) thecopy number of the CCNE1 gene.

The disclosure also features a method of evaluating the response of ahuman subject having, suspected of having, or at risk of developing adisease or disorder associated with CDK2 to a CDK2 inhibitor,comprising: (a) administering a CDK2 inhibitor to the human subject,wherein the human subject has been previously determined to have anamplification of the CCNE1 gene and/or an expression level of CCNE1 thatis higher than a control expression level of CCNE1; (b) measuring, in abiological sample of obtained from the subject subsequent to theadministering of step (a), the level of retinoblastoma (Rb) proteinphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3, wherein a reduced level of Rb phosphorylation at theserine corresponding to amino acid position 780 of SEQ ID NO:3, ascompared to a control level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3, is indicativethat the human subject responds to the CDK2 inhibitor. In someembodiments, the subject has a disease or disorder associated with CDK2.In some embodiments, the subject is suspected of having or is at risk ofdeveloping a disease or disorder associated with CDK2. In someembodiments, the biological sample comprises a blood sample or a tumorbiopsy sample.

Phosphorylation of Rb at the serine corresponding to amino acid position780 of SEQ ID NO:3 (referred to herein as “Ser780” or “S780”) has beenidentified in the Examples as a pharmacodynamic marker useful inassessing responsiveness (e.g., inhibition by CDK2) of a human subjecthaving a disease or disorder having CCNE1 amplification to a CDK2inhibitor.

Rb is a regulator of the cell cycle and acts as a tumor suppressor. Rbis activated upon phosphorylation by cyclin D-CDK4/6 at Ser780 andSer795 and by cyclin E/CDK2 at Ser807 and Ser811. Rb is encoded by theRB transcriptional corepressor 1 (“RB1”) gene (GenBank Accession No.NM_000321). The amino acid sequence of human Rb is provided below(GenBank Accession No. NP_000312/UniProtKB Accession No. P06400) (S780is in bold and underlined):

(SEQ ID NO: 3)  1 MPPKTPRKTA ATAAAAAAEP PAPPPPPPPE EDPEQDSGPE DLPLVRLEFE ETEEPDFTAL 61 CQKLKIPDHV RERAWLTWEK VSSVDGVLGG YIQKKKELWG ICIFIAAVDL DEMSFTFTEL121 QKNIEISVHK FFNLLKEIDT STKVDNAMSR LLKKYDVLFA LFSKLERTCE LIYLTQPSSS181 ISTEINSALV LKVSWITFLL AKGEVLQMED DLVISFQLML CVLDYFIKLS PPMLLKEPYK241 TAVIPINGSP RTPRRGQNRS ARIAKQLEND TRIIEVLCKE HECNIDEVKN VYFKNFIPFM301 NSLGLVTSNG LPEVENLSKR YEEIYLKNKD LDARLFLDHD KTLQTDSIDS FETQRTPRKS361 NLDEEVNVIP PHTPVRTVMN TIQQLMMILN SASDQPSENL ISYFNNCTVN PKESILKRVK421 DIGYIFKEKF AKAVGQGCVE IGSQRYKLGV RLYYRVMESM LKSEEERLSI QNFSKLLNDN481 IFHMSLLACA LEVVMATYSR STSQNLDSGT DLSFPWILNV LNLKAFDFYK VIESFIKAEG541 NLTREMIKHL ERCEHRIMES LAWLSDSPLF DLIKQSKDRE GPTDHLESAC PLNLPLQNNH601 TAADMYLSPV RSPKKKGSTT RVNSTANAET QATSAFQTQK PLKSTSLSLF YKKVYRLAYL661 RLNTLCERLL SEHPELEHII WTLFQHTLQN EYELMRDRHL DQIMMCSMYG ICKVKNIDLK721 FKIIVTAYKD LPHAVQETFK RVLIKEEEYD SIIVFYNSVF MQRLKTNILQ YASTRPPTLS781 PIPHIPRSPY KFPSSPLRIP GGNIYISPLK SPYKISEGLP TPTKMTPRSR ILVSIGESFG841 TSEKFQKINQ MVCNSDRVLK RSAEGSNPPK PLKKLRFDIE GSDEADGSKH LPGESKFQQK901 LAEMTSTRTR MQKQKMNDSM DTSNKEEK.

As stated above, the Examples demonstrate CDK2-knockdown inhibitsproliferation in CCNE1-amplified cell lines, but not inCCNE1-non-amplified cell lines. The Examples further demonstrateCDK2-knockdown or inhibition blocks Rb phosphorylation at the S780 inCCNE1-amplified cell lines, but not in CCNE1-non-amplified cell lines.Accordingly, Rb phosphorylation at the serine corresponding to aminoacid position 780 of SEQ ID NO:3 is a pharmacodynamic marker forassessing response to CDK2 inhibition in CCNE1 amplified cancer cells orpatients with diseases or disorders having CCNE1 amplification. Thus,provided herein are methods relating to the use of the level of Rbphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3 in a human subject having, suspected of having, or atrisk of developing a disease or disorder associated with CDK2 as amarker for indicating the response of the human subject to a CDK2inhibitor, wherein the human subject has an increased expression levelof CCNE1.

Thus, the disclosure features a method for measuring the amount of aprotein in a sample, comprising: (a) providing a biological sampleobtained from a human subject having a disease or disorder associatedwith CDK2; and (b) measuring the level of Rb protein phosphorylation atthe serine corresponding to amino acid position 780 of SEQ ID NO:3 inthe biological sample. In some embodiments, the biological samplecomprises a blood sample or a tumor biopsy sample. In a specificembodiment, provided herein is a method of evaluating the response of ahuman subject having, suspected of having, or at risk of developing adisease or disorder associated with CDK2 to a CDK2 inhibitor,comprising: (a) administering a CDK2 inhibitor to the human subject,wherein the human subject has been previously determined to have anamplification of the CCNE1 gene and/or an expression level of CCNE1 thatis higher than a control expression level of CCNE1; and (b) measuring,in a biological sample obtained from the human subject subsequent to theadministering of step (a), the level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3, wherein areduced level of Rb phosphorylation at the serine corresponding to aminoacid position 780 of SEQ ID NO:3, as compared to a control level of Rbphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3, is indicative that the human subject responds to theCDK2 inhibitor. In specific embodiments, the human subject has a diseaseor disorder associated with CDK2.

A reduced level of Rb phosphorylation at the serine corresponding toamino acid position 780 of SEQ ID NO:3, as compared to a control levelof Rb phosphorylation at the serine corresponding to amino acid position780 of SEQ ID NO:3, combined with an amplification of the CCNE1 geneand/or an expression level of CCNE1 that is higher than a controlexpression level of CCNE1, is indicative that a human subject having,suspected of having, or at risk of developing a disease or disorderassociated with CDK2 responds to a CDK2 inhibitor. For example, in asubject having an amplification of the CCNE1 gene and/or an expressionlevel of CCNE1 that is higher than a control expression level of CCNE1,a biological sample, obtained from the subject after treatment with aCDK2 inhibitor, having low (e.g., reduced as compared to a control) orundetectable levels of Rb phosphorylation at serine corresponding toamino acid position 780 of SEQ ID NO:3 is indicative that the subjectresponds to the CDK2 inhibitor.

A biological sample, obtained from a subject after administration of aCDK2 inhibitor to the subject, having a reduced level of Rbphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3, as compared to a control level of Rb phosphorylation atthe serine corresponding to amino acid position 780 of SEQ ID NO:3,combined with: (i) an amplification of the CCNE1 gene and/or anexpression level of CCNE1 that is higher than a control expression levelof CCNE1, and (ii) presence of a CDKN2A gene encoding a p16 proteincomprising the amino acid sequence of SEQ ID NO:1, presence of a CDKN2Agene lacking one or more inactivating nucleic acid substitutions and/ordeletions, and/or presence of a p16 protein (e.g., a p16 proteincomprising the amino acid sequence of SEQ ID NO:1), is indicative that ahuman subject having, suspected of having, or at risk of developing adisease or disorder associated with CDK2 responds to a CDK2 inhibitor.For example, in a human subject having (i) an amplification of the CCNE1gene and/or an expression level of CCNE1 that is higher than a controlexpression level of CCNE1, and (ii) the presence of a CDKN2A geneencoding a p16 protein comprising the amino acid sequence of SEQ IDNO:1, the presence of a CDKN2A gene lacking one or more inactivatingnucleic acid substitutions and/or deletions, and/or the presence of ap16 protein (e.g., a p16 protein comprising the amino acid sequence ofSEQ ID NO: 1), a biological sample, obtained from the human subjectafter administration of a CDK2 inhibitor to the subject, having low(e.g., reduced as compared to a control) or undetectable levels of Rbphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3 is indicative that the human subject responds to the CDK2inhibitor

In some embodiments, the CCNE1 gene is amplified to a gene copy numberfrom 3 to 25. In specific embodiments, the CCNE1 gene is amplified to agene copy number of at least 3. In specific embodiments, the CCNE1 geneis amplified to a gene copy number of at least 5. In specificembodiments, the CCNE1 gene is amplified to a gene copy number of atleast 7. In specific embodiments, the CCNE1 gene is amplified to a genecopy number of at least 10. In specific embodiments, the CCNE1 gene isamplified to a gene copy number of at least 12. In specific embodiments,the CCNE1 gene is amplified to a gene copy number of at least 14. Inspecific embodiments, the CCNE1 gene is amplified to a gene copy numberof at least 21. In specific embodiments, the expression level of CCNE1is the level of CCNE1 mRNA. In specific embodiments, the expressionlevel of CCNE1 is the level of CCNE1 protein.

Controls

As described above, the methods related to biomarkers andpharmacodynamic markers can involve, measuring one or more markers(e.g., a biomarker or a pharmacodynamics marker, e.g., the amplificationof the CCNE1 gene, the expression level of CCNE1, the presence of aCDKN2A gene encoding a p16 protein comprising the amino acid sequence ofSEQ ID NO: 1, the presence of a CDKN2A gene lacking one or moreinactivating nucleic acid substitutions and/or deletions, the presenceof a p16 protein (e.g., a p16 protein comprising the amino acid sequenceof SEQ ID NO:1), and Rb phosphorylation at the serine corresponding toamino acid position 780 of SEQ ID NO:3) in a biological sample from ahuman subject having, suspected of having or at risk of developing adisease or disorder associated with CDK2. In specific embodiments, thehuman subject has a disease or disorder associated with CDK2. Inspecific embodiments, the human subject is suspected of having or is atrisk of developing a disease or disorder associated with CDK2. Incertain aspects, the level (e.g., amplification (e.g., for the CCNE1gene), expression level (e.g., for CCNE1 or p16 protein), orphosphorylation level (e.g., for Rb)) of one or more biomarkers,compared to a control level of the one or more biomarkers,predicts/indicates the response of a human subject to treatmentcomprising a CDK2 inhibitor. In certain embodiments, when (i) the CCNE1gene is amplified and/or an expression level of CCNE1 that is higherthan a control expression level of CCNE1, and (ii) a CDKN2A geneencoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1is present, a CDKN2A gene lacking one or more inactivating nucleic acidsubstitutions and/or deletions is present, and/or a p16 protein (e.g., ap16 protein comprising the amino acid sequence of SEQ ID NO:1) ispresent, the human subject is identified as likely to respond to a CDK2inhibitor. In other embodiments, when (i) the CCNE1 gene is amplifiedand/or an expression level of CCNE1 that is higher than a controlexpression level of CCNE1, and (ii) in a biological sample from thehuman subject after the human subject has been administered a CDK2inhibitor, the level of Rb phosphorylation at the serine correspondingto amino acid position 780 of SEQ ID NO:3 is less than the control levelof Rb phosphorylation at the serine corresponding to amino acid position780 of SEQ ID NO:3, the human subject is identified as responding to aCDK2 inhibitor. In yet another embodiment, when (i) the CCNE1 gene isamplified and/or an expression level of CCNE1 that is higher than acontrol expression level of CCNE1, (ii) a CDKN2A gene encoding a p16protein comprising the amino acid sequence of SEQ ID NO: 1 is present, aCDKN2A gene lacking one or more inactivating nucleic acid substitutionsand/or deletions is present, and/or a p16 protein (e.g., a p16 proteincomprising the amino acid sequence of SEQ ID NO:1) is present, and (iii)in a biological sample from the human subject after the human subjecthas been administered a CDK2 inhibitor, the level of Rb phosphorylationat the serine corresponding to amino acid position 780 of SEQ ID NO:3 isless than the control level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3, the humansubject is identified as responding to a CDK2 inhibitor. In thiscontext, the term “control” includes a sample (from the same tissuetype) obtained from a human subject who is known to not respond to aCDK2 inhibitor. The term “control” also includes a sample (from the sametissue type) obtained in the past from a human subject who is known tonot respond to a CDK2 inhibitor and used as a reference for futurecomparisons to test samples taken from human subjects for whichtherapeutic responsiveness is to be predicted. The “control” level(e.g., gene copy number, expression level, or phosphorylation level) fora particular biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in aparticular cell type or tissue may be pre-established by an analysis ofbiomarker level (e.g., expression level or phosphorylation level) in oneor more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 ormore) human subjects that have not responded to treatment with a CDK2inhibitor. This pre-established reference value (which may be an averageor median level (e.g., gene copy number, expression level, orphosphorylation level) taken from multiple human subjects that have notresponded to the therapy) may then be used for the “control” level ofthe biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in thecomparison with the test sample. In such a comparison, the human subjectis predicted to respond to a CDK2 inhibitor if the CCNE1 gene isamplified and/or the expression level of CCNE is higher than thepre-established reference, and a CDKN2A gene encoding a p16 proteincomprising the amino acid sequence of SEQ ID NO:1 is present, a CDKN2Agene lacking one or more inactivating nucleic acid substitutions and/ordeletions is present, and/or a p16 protein (e.g., a p16 proteincomprising the amino acid sequence of SEQ ID NO:1) is present. Inanother such a comparison, the human subject is predicted to respond toa CDK2 inhibitor if (i) CCNE1 gene is amplified and/or the expressionlevel of CCNE is higher than the pre-established reference, and (ii)after administering to the human subject a CDK2 inhibitor, the level ofRb phosphorylation at the serine corresponding to amino acid position780 of SEQ ID NO:3 is lower than the pre-established reference. In yetanother such a comparison, the human subject is indicated to respond toa CDK2 inhibitor if (i) CCNE1 gene is amplified and/or the expressionlevel of CCNE is higher than the pre-established reference, (ii) aCDKN2A gene encoding a p16 protein comprising the amino acid sequence ofSEQ ID NO:1 is present, a CDKN2A gene lacking one or more inactivatingnucleic acid substitutions and/or deletions is present, and/or a p16protein (e.g., a p16 protein comprising the amino acid sequence of SEQID NO:1) is present, and (iii) after administering to the human subjecta CDK2 inhibitor, the level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3 is lower thanthe pre-established reference.

The “control” level for a particular biomarker in a particular cell typeor tissue may alternatively be pre-established by an analysis ofbiomarker level in one or more human subjects that have responded totreatment with a CDK2 inhibitor. This pre-established reference value(which may be an average or median level (e.g., expression level orphosphorylation level) taken from multiple human subjects that haveresponded to the therapy) may then be used as the “control” level (e.g.,expression level or phosphorylation level) in the comparison with thetest sample. In such a comparison, the human subject is indicated torespond to a CDK2 inhibitor if the level (e.g., copy number of the CCNE1gene, expression level of CCNE1, expression level of p16, orphosphorylation level of Rb at the serine corresponding to amino acidposition 780 of SEQ ID NO:3) of the biomarker being analyzed is equal orcomparable to (e.g., at least 85% but less than 115% ol), thepre-established reference.

In certain embodiments, the “control” is a pre-established cut-offvalue. A cut-off value is typically a level (e.g., a copy number, anexpression level, or a phosphorylation level) of a biomarker above orbelow which is considered predictive of responsiveness of a humansubject to a therapy of interest. Thus, in accordance with the methodsand compositions described herein, a reference level (e.g., of CCNE1gene copy number, CCNE1 expression, p16 expression, or Rbphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3) is identified as a cut-off value, above or below ofwhich is predictive of responsiveness to a CDK2 inhibitor. Cut-offvalues determined for use in the methods described herein can becompared with, e.g., published ranges of concentrations but can beindividualized to the methodology used and patient population.

In some embodiments, the expression level of CCNE1 is increased ascompared to the expression level of CCNE1 in a control. For example, theexpression level of CCNE1 analyzed can be at least 1.5, at least 2, atleast 3, at least 4, at least 5, at least 6, at least 7, at least 8, atleast 9, at least 10, at least 20, at least 25, at least 50, at least75, or at least 100 times higher, or at least 10%, at least 20%, atleast 30%, at least 40%, at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, at least 100%, at least 200%, at least 300%, atleast 400%, at least 500%, at least 600%, at least 700%, at least 800%,at least 900%, at least 1,000%, at least 1,500%, at least 2,000%, atleast 2,500%, at least 3,000%, at least 3,500%, at least 4,000%, atleast 4,500%, or at least 5,000% higher, than the expression level ofCCNE1 in a control.

A p16 protein is present if the protein is detectable by any assay knownin the art or described herein, such as, for example, western blot,immunohistochemistry, fluorescence-activated cell sorting, andenzyme-linked immunoassay. In some embodiments, a p16 protein is presentat an expression level that is within at least 5%, at least 10%, atleast 20%, or at least 30% of the p16 expression level in a healthycontrol.

In some embodiments, the level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3 being analyzedis reduced as compared to the level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3 in a control.For example, the level of the Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3 being analyzedcan be at least 1.5, at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 20,at least 25, at least 50, at least 75, or at least 100 times lower, orat least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, or 100% lower, thanthe level of Rb phosphorylation at the serine corresponding to aminoacid position 780 of SEQ ID NO:3 in a control.

Biological Samples

Suitable biological samples for the methods described herein include anysample that contains blood or tumor cells obtained or derived from thehuman subject in need of treatment. For example, a biological sample cancontain tumor cells from biopsy from a patient suffering from a solidtumor. A tumor biopsy can be obtained by a variety of means known in theart. Alternatively, a blood sample can be obtained from a patientssuffering from a hematological cancer.

A biological sample can be obtained from a human subject having,suspected of having, or at risk of developing, a disease or disorderassociated with CDK2. In some embodiments, the disease or disorderassociated with CDK2 is a cancer (such as those described supra).

Methods for obtaining and/or storing samples that preserve the activityor integrity of molecules (e.g., nucleic acids or proteins) in thesample are well known to those skilled in the art. For example, abiological sample can be further contacted with one or more additionalagents such as buffers and/or inhibitors, including one or more ofnuclease, protease, and phosphatase inhibitors, which preserve orminimize changes in the molecules in the sample.

Evaluating Biomarkers and Pharmacodynamic Markers

Expression levels of CCNE1 or p16 can be detected as, e.g., RNAexpression of a target gene (i.e., the genes encoding CCNE1 or p16).That is, the expression level (amount) of CCNE1 or p16 can be determinedby detecting and/or measuring the level of mRNA expression of the geneencoding CCNE1. Alternatively, expression levels of CCNE1 or p16 can bedetected as, e.g., protein expression of target gene (i.e., the genesencoding CCNE1 or p16). That is, the expression level (amount) of CCNE1or p16 can be determined by detecting and/or measuring the level ofprotein expression of the genes encoding CCNE1 or p16.

In some embodiments, the expression level of CCNE1 or p16 is determinedby measuring RNA levels. A variety of suitable methods can be employedto detect and/or measure the level of mRNA expression of a gene. Forexample, mRNA expression can be determined using Northern blot or dotblot analysis, reverse transcriptase-PCR (RT-PCR; e.g., quantitativeRT-PCR), in situ hybridization (e.g., quantitative in situhybridization), nucleic acid array (e.g., oligonucleotide arrays or genechips) and RNA sequencing analysis. Details of such methods aredescribed below and in, e.g., Sambrook et al., Molecular Cloning: ALaboratory Manual Second Edition vol. 1, 2 and 3. Cold Spring HarborLaboratory Press: Cold Spring Harbor, N.Y., USA, November 1989; Gibsonet al. (1999) Genome Res., 6(10):995-1001; and Zhang et al. (2005)Environ. Sci. Technol., 39(8):2777-2785; U.S. Publication No.2004086915; European Patent No. 0543942; and U.S. Pat. No. 7,101,663;Kukurba et al. (2015) Cold Spring Harbor Protocols, 2015 (11): 951-69;the disclosures of each of which are incorporated herein by reference intheir entirety.

In one example, the presence or amount of one or more discrete mRNApopulations in a biological sample can be determined by isolating totalmRNA from the biological sample (see, e.g., Sambrook et al. (supra) andU.S. Pat. No. 6,812,341) and subjecting the isolated mRNA to agarose gelelectrophoresis to separate the mRNA by size. The size-separated mRNAsare then transferred (e.g., by diffusion) to a solid support such as anitrocellulose membrane. The presence or amount of one or more mRNApopulations in the biological sample can then be determined using one ormore detectably-labeled-polynucleotide probes, complementary to the mRNAsequence of interest, which bind to and thus render detectable theircorresponding mRNA populations. Detectable-labels include, e.g.,fluorescent (e.g., umbelliferone, fluorescein, fluoresceinisothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansylchloride, allophycocyanin, or phycoerythrin), luminescent (e.g.,europium, terbium, Qdot™ nanoparticles supplied by the Quantum DotCorporation, Palo Alto, Calif.), radiological (e.g., 125I, 131I, 35S,32P, 33P, or 3H), and enzymatic (horseradish peroxidase, alkalinephosphatase, beta-galactosidase, or acetylcholinesterase) labels.

In some embodiments, the expression level of CCNE1 or p16 is determinedby measuring protein levels. A variety of suitable methods can beemployed to detect and/or measure the level of protein expression oftarget genes. For example, CCNE1 or p16 protein expression can bedetermined using western blot, enzyme-linked immunosorbent assay(“ELISA”), fluorescence activated cell sorting, or immunohistochemistryanalysis (e.g., using a CCNE1-specific or p16-specific antibody,respectively). Details of such methods are described below and in, e.g.,Sambrook et al., supra.

In one example, the presence or amount of one or more discrete proteinpopulations (e.g., CCNE1 or p16) in a biological sample can bedetermined by western blot analysis, e.g., by isolating total proteinfrom the biological sample (see, e.g., Sambrook et al. (supra)) andsubjecting the isolated protein to agarose gel electrophoresis toseparate the protein by size. The size-separated proteins are thentransferred (e.g., by diffusion) to a solid support such as anitrocellulose membrane. The presence or amount of one or more proteinpopulations in the biological sample can then be determined using one ormore antibody probes, e.g., a first antibody specific for the protein ofinterest (e.g., CCNE1 or p16), and a second antibody, detectablylabeled, specific for the first antibody, which binds to and thusrenders detectable the corresponding protein population.Detectable-labels suitable for use in western blot analysis are known inthe art.

Methods for detecting or measuring gene expression (e.g., mRNA orprotein expression) can optionally be performed in formats that allowfor rapid preparation, processing, and analysis of multiple samples.This can be, for example, in multi-welled assay plates (e.g., 96 wellsor 386 wells) or arrays (e.g., nucleic acid chips or protein chips).Stock solutions for various reagents can be provided manually orrobotically, and subsequent sample preparation (e.g., RT-PCR, labeling,or cell fixation), pipetting, diluting, mixing, distribution, washing,incubating (e.g., hybridization), sample readout, data collection(optical data) and/or analysis (computer aided image analysis) can bedone robotically using commercially available analysis software,robotics, and detection instrumentation capable of detecting the signalgenerated from the assay. Examples of such detectors include, but arenot limited to, spectrophotometers, luminometers, fluorimeters, anddevices that measure radioisotope decay. Exemplary high-throughputcell-based assays (e.g., detecting the presence or level of a targetprotein in a cell) can utilize ArrayScan® VTI HCS Reader or KineticScan®HCS Reader technology (Cellomics Inc., Pittsburgh, Pa.).

In some embodiments, the presence of a CDKN2A gene encoding a p16protein comprising the amino acid sequence of SEQ ID NO:1 and/or thepresence of a CDKN2A gene lacking one or more inactivating nucleic acidsubstitutions and/or deletions is determined by evaluating the DNAsequence of the CDKN2A gene (e.g., genomic DNA or cDNA) or by evaluatingthe RNA sequence of the CDKN2A gene (e.g., RNA, e.g., mRNA). Methods ofperforming nucleic acid sequencing analyses are known in the art anddescribed above. Nonlimiting examples of inactivating nucleic acidsubstitutions and/or deletions preventing the CDKN2A gene from encodinga protein comprising the amino acid sequence of SEQ ID NO:1 aredescribed in Table A, above. In specific embodiments, the one or moreinactivating nucleic acid substitutions and/or deletions in the CDKN2Agene is as described in Yarbrough et al., Journal of the National CancerInstitute, 91 (18): 1569-1574, 1999; Liggett and Sidransky, Biology ofNeoplasia, Journal of Oncology, 16(3): 1197-1206, 1998, and Cairns etal., Nature Genetics, 11:210-212, 1995, each of which is incorporated byreference herein in its entirety.

In some embodiments, the expression level of a gene or the presence of agene lacking one or more inactivating nucleic acid substitutions ordeletions is determined by evaluating the copy number variation (CNV) ofthe gene. The CNV of genes (e.g., the CCNE1 gene and/or the CDKN2A gene)can be determined/identified by a variety of suitable methods. Forexample, CNV can be determined using fluorescent in situ hybridization(FISH), multiplex ligation dependent probe amplification (MLPA), arraycomparative genomic hybridization (aCGH), single-nucleotidepolymorphisms (SNP) array, and next-generation sequencing (NGS)technologies.

In one example, the copy number variation of one or more discrete genesin a biological sample can be determined by MLPA, e.g., by extractingDNA specimens from the biological sample (see, e.g., Sambrook et al.(supra) and U.S. Pat. No. 6,812,341), and amplifying DNA sequence ofinterest (e.g., CCNE1 or CDKN2A) using a mixture of MLPA probes. EachMLPA probe consists of two oligonucleotides that hybridize toimmediately adjacent target DNA sequence (e.g., CCNE1 or CDKN2A) inorder to be ligated into a single probe. Ligated probes are amplifiedthough PCR with one PCR primer fluorescently labeled, enabling theamplification products to be visualized during fragment separation bycapillary electrophoresis. The presence, absence or amplification of oneor more genes of interest in the biological sample is calculated bymeasuring PCR derived fluorescence, quantifying the amount of PCRproduct after normalization and comparing it with control DNA samples.

The level of Rb phosphorylation at the serine corresponding to aminoacid position 780 of SEQ ID NO:3 can be detected by a variety ofsuitable methods. For example, phosphorylation status can be determinedusing western blot, ELISA, fluorescence activated cell sorting, orimmunohistochemistry analysis. Details of such methods are describedbelow and in, e.g., Sambrook et al., supra.

As with the methods for detecting or measuring gene expression (above),methods for detecting or measuring the level of Rb phosphorylation atthe serine corresponding to amino acid position 780 of SEQ ID NO:3 canoptionally be performed in formats that allow for rapid preparation,processing, and analysis of multiple samples.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.,“Two-Pump at-Column Dilution Configuration for Preparative LC-MS,” K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification,” K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization,” K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature (see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization,” K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature (See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization,” K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)). Typically, the flow rate used with the 30×100 mmcolumn was 60 mL/minute.

Intermediate 1. tert-Butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (11.4 g, 52.5mmol) in tert-butanol (100 mL) and 1,2-dichloroethane (100 mL) wascooled to 0° C. in an ice bath before a 1 molar solution of zincchloride (75 mL, 75 mmol) in diethyl ether was added and the resultingmixture was purged with nitrogen and stirred at 0° C. for 1 hour. To thereaction mixture was then added tert-butyl4-aminopiperidine-1-carboxylate (10.0 g, 49.9 mmol), followed by dropwise addition of a solution of triethylamine (8.35 mL, 59.9 mmol) in a1:1 mixture of 1,2-dichloroethane/tort-butanol (15 mL). The ice bath wasthen removed and the reaction mixture was allowed to warm to r.t. beforeheating to 60° C. overnight. After cooling to r.t., the reaction mixturewas then concentrated to approximately 1/3 volume and diluted withwater. Upon stirring an off-white precipitate formed and the mixture wasslurried for 1 hour. The precipitate was then collected via filtration,washed with water and hexanes, and dried under air. The crude productobtained was used directly without further purification. LCMS calculatedfor C₁₁H₁₃ClF₃N₄O₂ (M+1-C₄H₈)⁺: m/z=325.1; found 325.0.

Intermediate 2.N-(Piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(600 mg, 1.58 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole(652 mg, 2.36 mmol), Pd(dppf)Cl₂ DCM adduct (257 mg, 0.315 mmol), andsodium carbonate (334 mg, 3.15 mmol) in acetonitrile (5 mL) and water (1mL) was purged with nitrogen and irradiated in a microwave reactor at100° C. for 30 minutes. After cooling to r.t., the reaction mixture wasdiluted with water and extracted with CH₂Cl₂. The combined organicphases were then dried over MgSO₄ and concentrated. Then, a 4 molarsolution of HCl in 1,4-dioxane (3 mL) was added to the crude residue andthe mixture was stirred at r.t. for 1 hour. The mixture was then dilutedwith water (10 mL) and the aqueous layer was extracted with CH₂Cl₂. Theorganic layer was removed and the aqueous layer was made basic via theaddition of a 50% aqueous solution of NaOH. The aqueous layer was thenextracted with EtOAc and CH₂Cl₂ and the combined organic phases werewashed with brine, dried over MgSO₄, and concentrated. The crudematerial obtained was used directly without further purification. LCMScalculated for C₁₅H₁₇F₆N₆ (M+H)⁺: m/z=395.1; found 395.1.

Intermediate 3.N-(Piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 2, using1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazoleas starting material. LCMS calculated for C₁₈H₂₄F₃N₆O (M+H)⁺: m/z=397.2;Found 397.3.

Intermediate 4.4-Chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a flask with a stir bar, a mixture of2,4-dichloro-5-(trifluoromethyl)pyrimidine (9.18 g, 42.3 mmol) intert-butanol (81 mL) and 1,2-dichloroethane (81 mL) was cooled to 0° C.in an ice bath before a 1 molar solution of zinc chloride (60 mL, 60mmol) in diethyl ether was added and the resulting mixture was stirredat 0° C. for 1 hour. To the reaction mixture was then added1-(methylsulfonyl)piperidin-4-amine (7.18 g, 40.3 mmol), followed bydropwise addition of a solution of triethylamine (6.74 mL, 48.3 mmol) ina 1:1 mixture of 1,2-dichloroethane/tort-butanol (7 mL). The ice bathwas then removed and the reaction mixture was allowed to warm to r.t.before heating to 60° C. overnight. The reaction mixture was thenconcentrated to approximately 1/3 volume and diluted with water. Anoff-white precipitate formed and the mixture was slurried for 2 hours.The precipitate was then collected via filtration, washed with water,and dried under air. The crude product obtained was used directlywithout further purification. LCMS calculated for C₁₁H₁₅ClF₃N₄O₂S(M+H)⁺: m/z=359.1; Found: 359.0.

Intermediate 5. tert-Butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

In an oven-dried vial with a stir bar, a mixture of tert-butyl4-(4-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(200 mg, 0.502 mmol) in dry THF (5 mL) was purged with nitrogen andcooled to −78° C. in a dry ice/acetone bath before a 2.5 M solution ofBuLi (0.3 mL, 0.75 mmol) in hexanes was added dropwise. The reactionmixture was then stirred for 1 hour before2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.16 mL, 0.78mmol) was added dropwise, and the mixture was stirred at −78° C. for 30minutes. The dry ice/acetone bath was then removed and the mixture waswarmed to r.t. and stirred for an additional 30 minutes. Following this,the reaction mixture was quenched via the addition of saturated aqueousNH₄Cl. The mixture was then extracted with CH₂Cl₂, and the combinedorganic phases were dried over MgSO₄ and concentrated. The crudematerial obtained was used without further purification. LCMS calculatedfor C₁₆H₂₄BF₃N₃O₄ (M+1-C₄H₈)⁺: m/z=390.2; Found 390.2.

Intermediate 6. tert-Butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 5, using tert-butyl4-(4-bromo-5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylateinstead of tert-butyl4-(4-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylateas starting material. LCMS calculated for C₁₆H₂₄BF₃N₃O₄ (M+1-C₄H₈)⁺:m/z=390.2; Found 390.3.

Intermediate 7.2-Chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine

A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.03 g, 9.35mmol),1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.00 g, 7.19 mmol), Pd(dppf)Cl₂ DCM adduct (587 mg, 0.719 mmol), andsodium carbonate (1.53 g, 14.4 mmol) in acetonitrile (20 mL) and water(4.0 mL) was purged under nitrogen at r.t. before heating to 80° C.overnight. After cooling to r.t., the crude reaction mixture wasconcentrated under reduced pressure and then partitioned between CH₂Cl₂and water. Using a separatory funnel, the aqueous layer was extractedwith CH₂Cl₂ (20 mL×3). The combined CH₂Cl₂ fractions were dried overNa₂SO₄, concentrated under reduced pressure, then purified via flashcolumn chromatography (Agela Flash Column Silica-CS (120 g), elutingwith a gradient of 0 to 20% EtOAc/hexanes). LCMS calculated forC₁₃H₁₃ClF₃N₄O (M+H)⁺: m/z=333.1; Found 333.0. ¹H NMR (500 MHz, DMSO-d₆)δ 9.06 (s, 1H), 8.53 (s, 1H), 8.06 (s, 1H), 4.70-4.53 (tt, J=10.2, 5.7Hz, 1H), 4.02-3.92 (m, 2H), 3.50-3.41 (dd, J=14.6, 11.3 Hz, 2H),2.10-1.87 (m, 4H). ¹⁹F NMR (470 MHz, DMSO-d₆) δ −60.60. ¹³C NMR (126MHz, DMSO-d₆) δ 162.7 (s), 159.5 (s), 159.1 (q, J=6.0 Hz), 139.7 (q,J=3.9 Hz), 132.0 (d, 0.7=3.3 Hz), 123.3 (d, j=272.9 Hz), 116.3 (q,j=32.5 Hz), 116.4 (s), 65.8 (s), 57.8 (s), 32.5 (s).

Intermediate 8.2,5-Dichloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidine

A mixture of 2,4,5-trichloropyrimidine (0.330 g, 1.80 mmol),1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.50 g, 1.80 mmol) and sodium carbonate (0.381 g, 3.60 mmol) inacetonitrile (5 mL) and water (1 mL) was degassed with nitrogen for 3minutes before Pd(dppf)Cl₂ DCM adduct (0.147 g, 0.180 mmol) was addedand the mixture was degassed with nitrogen for an additional 2 minutes.The reaction mixture was then sealed and stirred at 80° C. for 2 hours.After cooling to r.t., the reaction mixture was concentrated andpurified by Biotage Isolera™. LCMS calculated for C₁₂H₁₃Cl₂N₄O (M+H)⁺:m/z=299.0; Found: 299.0.

Intermediate 9.N-(1-(Methylsulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 4, 2.0 g, 5.57 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(2.13 g, 7.25 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2) (131 mg, 0.167 mmol), and potassium phosphate, tribasic(4.73 g, 22.3 mmol) in 1,4-dioxane (11.6 mL) and water (2.3 mL) waspurged with nitrogen and irradiated in a microwave reactor at 110° C.for 2 hours. After cooling to r.t., the reaction mixture was filteredover a pad of celite and the filter cake was washed with EtOAc. Thefiltrate was then transferred to a separatory funnel and the organicphase was washed with 1 molar NaOH and brine, dried over MgSO₄, andconcentrated. To the crude residue was added CH₂Cl₂ and Et₂O, and theresulting precipitate was slurried for 30 minutes, then collected viafiltration, washed with hexanes, and dried under air. The crude materialobtained was used without further purification. LCMS calculated forC₁₄H₁₈F₃N₆O₂S (M+H)⁺: m/z=391.1; Found 391.2.

Intermediate 10.N-(cis-3-(tort-Butyldimethylsilyloxy)-1-methylcyclobutyl)-5-fluoro-6-methylpicolinamide

To a solution of 5-fluoro-6-methylpicolinic acid (500 mg, 3.22 mmol) andN-methylmorpholine (0.89 mL, 8.06 mmol) in CH₂Cl₂ (0.5 M) at 0° C. wasadded isobutyl chloroformate (0.508 mL, 3.87 mmol) and the reactionmixture was stirred at 0° C. for 20 minutes before a mixture ofcis-3-aminocyclobutan-1-ol hydrochloride in CH₂Cl₂ (1.5 M) was added.The solution was then allowed to warm to r.t. and stirred overnight. Thereaction was then quenched by the addition of saturated aqueous NaHCO₃,and the aqueous layer was removed using a phase separator. The organicfraction was concentrated, and the crude residue was then redissolved inCH₂Cl₂ (0.5 M) and tert-butyldimethylsilyl chloride (TBS-Cl) (0.729 g,4.83 mmol) and imidazole (0.351 g, 5.16 mmol) were added. The reactionmixture was stirred at r.t. for 2 hours. The reaction was then quenchedby the addition of saturated aqueous NaHCO₃, and the aqueous layer wasremoved using a phase separator. The organic fraction was concentratedand purified via flash column chromatography (Agela Flash ColumnSilica-CS (40 g), eluting with a gradient of 0 to 15% EtOAc/hexanes).LCMS calculated for C₁₈H₃₀FN₂O₂Si (M+H)⁺: m/z=353.2; Found 353.2.

Intermediate 11.4-Chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 1, 3.00 g, 7.88 mmol) in THF (39.4 mL) was purged withnitrogen and stirred at 80° C. for 10 minutes before a 4 molar solutionof HCl in 1,4-dioxane (7.88 mL, 31.5 mmol) was added and the reactionmixture was stirred at 80° C. for 2 hours. After cooling to r.t., thereaction mixture was sparged with nitrogen for 5 minutes before1-methyl-1H-imidazole-4-sulfonyl chloride (1.71 g, 9.47 mmol) was addedfollowed by dropwise addition of triethylamine (6.59 mL, 47.3 mmol), andthe mixture was stirred at r.t. for 1 hour. The reaction mixture wasthen diluted with water and extracted with EtOAc and CH₂Cl₂. Thecombined organic phases were then dried over MgSO₄ and concentrated. Thecrude material obtained was used directly without further purification.LCMS calculated for C₁₄H₁₇ClF₃N₆O₂S (M+H)⁺: m/z=425.1; Found 425.1.

Intermediate 12.N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a microwave vial with a stir bar, a mixture of4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 11, 2.5 g, 5.88 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(2.60 g, 8.83 mmol), XPhos Pd G2 (139 mg, 0.177 mmol), and potassiumphosphate, tribasic (7.49 g, 35.3 mmol) in 1,4-dioxane (12.3 mL) andwater (2.46 mL) was degassed with nitrogen and irradiated in a microwavereactor at 110° C. for 2 hours. Following this, the reaction temperaturewas increased to 130° C. and microwave irradiation was continued for anadditional 30 minutes. After cooling to r.t., the reaction mixture waspoured into ethyl acetate (30 mL), and the resulting mixture wasfiltered over a pad of celite and the filter cake was washed with ethylacetate (30 mL). The filtrate was then transferred to a separatoryfunnel and the organic phase was washed with brine (5 mL), dried overMgSO₄, and concentrated. To the crude residue was added CH₂Cl₂ (15 mL)followed by Et₂O (150 mL), and the resulting precipitate was collectedvia filtration, washed with hexanes, and dried under air. The crudematerial obtained was used directly without further purification. LCMScalculated for C₁₇H₂₀F₃N₈O₂S (M+H)⁺: m/z=457.2; Found 457.1.

Intermediate 13. tert-Butyl4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of 2,4-dichloropyrimidine-5-carbonitrile (23.89 g, 137 mmol)in tort-butanol (156 mL) and 1,2-dichloroethane (156 mL) was cooled to0° C. in an ice bath before a 1 molar solution of zinc chloride (25.5 g,187 mmol) in diethyl ether was added and the resulting mixture waspurged with nitrogen and stirred at 0° C. for 1 hour. To the reactionmixture was then added tert-butyl 4-aminopiperidine-1-carboxylate (25 g,125 mmol), followed by slow addition of a solution of Hunig's base (32.7mL, 187 mmol) in a 1:1 mixture of 1,2-dichloroethane/tort-butanol (15mL). The ice bath was then removed and the reaction mixture was allowedto warm to r.t. before heating to 60° C. overnight. After cooling tor.t., the reaction mixture was then concentrated to approximately 1/3volume and poured into rapidly stirred water. Upon stirring, aprecipitate formed and the mixture was slurried for 1 hour. Theprecipitate was then collected via filtration, washed with water andhexanes, and dried under air. The crude product obtained was useddirectly without further purification. LCMS calculated for C₁₁H₁₃ClN₅O₂(M+1-C₄H₈)⁺: m/z=282.1; found 282.0.

Intermediate 14. tert-Butyl4-((4,5-dichloropyrimidin-2-yl)amino)piperidine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 13, using 2,4,5-trichloropyrimidine instead of2,4-dichloropyrimidine-5-carbonitrile as starting material. LCMScalculated for C₁₀H₁₃Cl₂N₄O₂ (M+1-C₄H₈)⁺: m/z=291.0; Found: 291.0.

Intermediate 15. tert-Butyl(3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate

To a mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.093 g,5.04 mmol) in tort-butanol (7.64 mL), 1,2-dichloroethane (7.64 mL), andTHF (7.64 mL) was added zinc chloride (0.937 g, 6.87 mmol) and thereaction mixture was purged with nitrogen and stirred at 60° C. for 15minutes. After cooling to r.t., tert-butyl(3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate (1.00 g, 4.58 mmol) wasadded followed by drop wise addition ofN-ethyl-N-isopropylpropan-2-amine (1.20 mL, 6.87 mmol) and the reactionmixture was stirred at 60° C. overnight. After cooling to r.t., thereaction mixture was then diluted with water and extracted with CH₂Cl₂and EtOAc. The combined organic phases were dried over MgSO₄,concentrated, and purified via silica gel flash column chromatography(eluting with a gradient of EtOAc/hexanes). LCMS calculated forC₁₁H₁₂ClF₄N₄O₂ (M+1-C₄H₈)⁺: m/z=343.1; Found 343.0.

Intermediate 16. tert-Butyl(3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 15, using tert-butyl(3R,4S)-4-amino-3-methylpiperidine-1-carboxylate instead of tert-butyl(3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate as starting material.LCMS calculated for C₁₂H₁₅ClF₃N₄O₂ (M+1-C₄H₈)⁺: m/z=339.1; Found: 339.1.

Intermediate 17. tert-Butyl(3R,4S)-4-((4-chloro-5-cyanopyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 15, using 2,4-dichloropyrimidine-5-carbonitrile instead of2,4-dichloro-5-(trifluoromethyl)pyrimidine as starting material. LCMScalculated for C₁₁H₁₂ClFN₅O₂ (M+1-C₄H₈)⁺: m/z=300.1; Found: 300.0.

Intermediate 18. tert-Butyl(3R,4S)-4-((4-chloro-5-cyanopyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 15, using 2,4-dichloropyrimidine-5-carbonitrile instead of2,4-dichloro-5-(trifluoromethyl)pyrimidine and tert-butyl(3R,4S)-4-amino-3-methylpiperidine-1-carboxylate instead of tert-butyl(3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate as starting materials.LCMS calculated for C₁₂H₁₅ClN₅O₂ (M+1-C₄H₈)⁺: m/z=296.1; Found: 296.0.

Intermediate 19.1-(4-Methoxycyclohexyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of 4-methoxycyclohexan-1-ol (5.00 g, 38.4 mmol) in CH₂Cl₂ (192mL) was cooled to 0° C. in an ice bath before methanesulfonyl chloride(2.99 mL, 38.4 mmol) was added followed by dropwise addition of triethylamine (10.7 mL, 77 mmol). The ice bath was then removed, and thereaction mixture was purged with nitrogen and stirred at ambienttemperature overnight. The mixture was then diluted with saturatedaqueous NaHCO₃ and extracted with CH₂Cl₂. The combined organic layerswere then washed with 1 molar HCl and brine. The aqueous layer wasdiscarded and the organic layer was stirred with silica gel (5 g) for 30minutes, dried over MgSO₄, filtered, and concentrated. To a mixture ofthe crude residue and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.45 g,38.4 mmol) in CH₃CN (96 mL) was added cesium carbonate (25 g, 77 mmol)and the reaction mixture was purged with nitrogen and stirred at 100° C.overnight. After cooling to r.t., the reaction mixture was filtered andconcentrated. The crude residue was then purified by silica gel flashcolumn chromatography (eluting with a gradient of EtOAc/hexanes). LCMScalculated for C₁₆H₂₈BN₂O₃(M+H)⁺: m/z=307.2; Found: 307.2.

Intermediate 20. tert-Butyl4-((4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 1, 5.00 g, 13.1 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(5.79 g, 19.70 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2) (1.033 g, 1.313 mmol), and potassium phosphate, tribasic(11.13 g, 52.5 mmol) in 1,4-dioxane (23.28 mL) and water (4.66 mL) wasdegassed with nitrogen and irradiated in a microwave reactor at 100° C.for 2 hours. After cooling to r.t., the reaction mixture was dilutedwith water (30 mL) and extracted with ethyl acetate (6×30 mL). Thecombined organic layers were dried Na₂SO₄, filtered, and concentrated.To a stirred mixture of the crude residue in CH₂Cl₂ (50 mL) was slowlyadded hexanes (500 mL), and the resulting precipitate was collected viafiltration, washed with hexanes, and dried under air to affordtert-butyl4-((4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(3.45 g, 64% yield) as an off-white solid. LCMS calculated forC₁₈H₂₄F₃N₆O₂ (M+H)⁺: m/z=413.2; found 413.1.

Intermediate 21.4-(1H-Pyrazol-4-yl)-N-(1-(pyridin-2-ylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of tert-butyl4-((4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 20, 500 mg, 1.21 mmol) in 1,4-dioxane (6.06 mL) was addeda 4 molar solution of HCl in 1,4-dioxane (1.21 mL, 4.85 mmol) and thereaction mixture was stirred at 80° C. for 3 hours. The reaction mixturewas cooled to 0° C. before pyridine-2-sulfonyl chloride (215 mg, 1.212mmol) was added followed by dropwise addition of triethyl amine (1.01mL, 7.27 mmol). After stirring for 30 minutes, the reaction mixture wasadded dropwise to rapidly stirred water (100 mL). The resultingprecipitate was then collected via filtration in a sintered glassfunnel, and the filter cake was rinsed with water (2×5 mL) and driedunder vacuum. The crude material obtained was used directly withoutfurther purification. LCMS calculated for C₁₈H₁₉F₃N₇O₂S (M+H)⁺:m/z=454.1; found 454.1.

Intermediate 22.(1r,3r)-3-((tort-Butoxycarbonyl)amino)-3-methylcyclobutylmethanesulfonate

Step 1: tert-Butyl ((1r,3r)-3-hydroxy-1-methylcyclobutyl)carbamate

To a mixture of (1r,3r)-3-amino-3-methylcyclobutan-1-ol hydrochloride(200 mg, 1.45 mmol) and triethylamine (1013 μL, 7.27 mmol) in CH₂Cl₂(4.84 mL) was slowly added di-tert-butyl dicarbonate (337 μL, 1.453mmol) at 0° C. The resulting yellow solution was allowed to warm up tor.t. and stirred for 3 hours. Saturated aqueous NaHCO₃ (5 mL) was thenadded and the reaction mixture was extracted with CH₂Cl₂ (3×5 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The crude material obtained was then used directly withoutfurther purification. LCMS calculated for C₁₀H₂₀NO₃ (M+H)⁺: m/z=202.1;found 202.1.

Step 2: (1r,3r)-3-((tert-Butoxycarbonyl)amino)-3-methylcyclobutylmethanesulfonate

To a solution of tert-butyl((1r,3r)-3-hydroxy-1-methylcyclobutyl)carbamate (from step 1) andtriethylamine (1013 μL, 7.27 mmol) in CH₂Cl₂ (4.84 mL) was slowly addedmethanesulfonyl chloride (227 μL, 2.91 mmol) at 0° C. The resultingyellow solution was allowed to warm up to r.t. and stirred for 30minutes. Saturated aqueous NaHCO₃ (5 mL) was then added and the reactionmixture was extracted with CH₂Cl₂ (3×5 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated. The crude materialwas then purified by silica gel flash column chromatography (elutingwith a gradient of 20% to 100% EtOAc/hexanes) to give(1r,3r)-3-((tort-butoxycarbonyl)amino)-3-methylcyclobutylmethanesulfonate as a white solid. LCMS calculated for C₁₁H₂₂NO₅S(M+H)⁺: m/z=280.1; found 280.2.

Intermediate 23.3-Chloro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzaldehyde

To a mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.0 g,51.5 mmol) in DMF (103 mL) was added 3-chloro-4-fluorobenzaldehyde (16.3g, 103 mmol) and cesium carbonate (33.6 g, 103 mmol) and the reactionmixture was purged with nitrogen and stirred at 120° C. for 2 hours.After cooling to r.t., the mixture was then diluted with water andextracted with CH₂Cl₂. The combined organic layers were then washed withbrine, dried over MgSO₄, concentrated, and purified via silica gel flashcolumn chromatography (Agela Flash Column Silica-CS (330 g), elutingwith a gradient of 0 to 50% EtOAc/hexanes). LCMS calculated forC₁₆H₁₉BClN₂O₃ (M+H)⁺: m/z=333.1; Found: 333.1.

Intermediate 24.3-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzaldehyde

This compound was prepared according to the procedures described inIntermediate 23, using 4-fluoro-3-methylbenzaldehyde instead of3-chloro-4-fluorobenzaldehyde as starting material. LCMS calculated forC₁₇H₂₂BN₂O₃ (M+H)⁺: m/z=313.1; Found: 313.1.

Intermediate 25.6-Methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)picolinaldehyde

In an oven-dried flask with a stir bar, to a mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.60 g,18.5 mmol) in DMF (37.1 mL) was added 5-fluoro-6-methylpicolinaldehyde(2.58 g, 18.5 mmol) and potassium phosphate, tribasic (7.87 g, 37.1mmol) and the reaction mixture was purged with nitrogen and stirred at120° C. for 1 hour. After cooling to r.t., the mixture was then dilutedwith water and extracted with CH₂Cl₂. The combined organic layers werethen dried over MgSO₄ and concentrated. The crude residue was thenpurified via flash column chromatography (eluting with a gradient ofEtOAc/hexanes). LCMS calculated for C₁₆H₂₁BN₃O₃ (M+H)⁺: m/z=314.2;Found: 314.1.

Intermediate 26.4-Chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

To a mixture of 2,4-dichloropyrimidine-5-carbonitrile (15.0 g, 86 mmol)in tort-butanol (140 mL), 1,2-dichloroethane (140 mL), and THF (140 mL)was added zinc chloride (14.9 g, 109 mmol) and the reaction mixture wasstirred at 60° C. for 30 minutes. After cooling to r.t.,1-(methylsulfonyl)piperidin-4-amine (15.0 g, 84 mmol) was added followedby slow addition of A-ethyl-A-isopropylpropan-2-amine (19.1 mL, 109mmol) and the reaction mixture was stirred at 60° C. overnight. Aftercooling to r.t., the reaction mixture was then poured into Et₂O (700 mL)before hexanes (300 mL) was added, and the resulting precipitate wascollected via filtration, washed with Et₂O and water, and dried underair. The crude material obtained was used directly without furtherpurification. LCMS calculated for C₁₁H₁₅ClN₅O₂S (M+H)⁺: m/z=316.1;Found: 316.0.

Intermediate 27.4-(1-(2-Chloro-4-formylphenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

Step 1:4-Chloro-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

To a mixture of 2,4-dichloropyrimidine-5-carbonitrile (3.01 g, 17.3mmol) in tort-butanol (26.2 mL), 1,2-dichloroethane (26.2 mL), and THF(26.2 mL) was added zinc chloride (3.22 g, 23.6 mmol) and the reactionmixture was purged with nitrogen and stirred at 60° C. for 15 minutes.After cooling to r.t, 1-(ethylsulfonyl)piperidin-4-amine hydrochloride(3.6 g, 15.7 mmol) was added followed by drop wise addition ofN-ethyl-N-isopropylpropan-2-amine (8.22 mL, 47.2 mmol) and the reactionmixture was stirred at 60° C. overnight. After cooling to r.t., thereaction mixture was then diluted with water and extracted with EtOAc.The combined organic phases were dried over MgSO₄ and concentrated. Thecrude material obtained was used directly without further purification.LCMS calculated for C₁₂H₁₇ClN₅O₅S (M+H)⁺: m/z=330.1; found 330.0.

Step 2:4-(1-(2-Chloro-4-formylphenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

A mixture of4-chloro-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(from step 1),3-chloro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzaldehyde(Intermediate 23, 6.28 g, 18.89 mmol), Pd(dppf)Cl₂ CH₂Cl₂ adduct (1.286g, 1.574 mmol), and sodium carbonate (4.17 g, 39.3 mmol) in CH₃CN (65.5mL) and water (13.1 mL) was stirred at 80° C. overnight. After coolingto r.t., the mixture was diluted with water and extracted with EtOAc andCH₂Cl₂. The combined organic phases were then dried over MgSO₄ andconcentrated. The crude material obtained was then used directly withoutfurther purification. LCMS calculated for C₂₂H₂₃ClN₇O₃S (M+H)⁺:m/z=500.1; found 500.1.

Intermediate 28.4-Chloro-2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

This compound was prepared according to the procedures described inIntermediate 27, Step 1, using 1-(cyclopropylsulfonyl)piperidin-4-aminehydrochloride instead of 1-(ethylsulfonyl)piperidin-4-aminehydrochloride as starting material. LCMS calculated for C₁₃H₁₇ClN₅O₂S(M+H)⁺: m/z=342.1; Found: 342.0.

Intermediate 29.4-(1-(2-Chloro-4-formylphenyl)-1H-pyrazol-4-yl)-2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

A mixture of4-chloro-2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Intermediate 28, 800 mg, 2.34 mmol),3-chloro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzaldehyde(Intermediate 23, 778 mg, 2.34 mmol), Pd(dppf)Cl₂ CH₂Cl₂ adduct (191 mg,0.234 mmol), and sodium carbonate (744 mg, 7.02 mmol) in CH₃CN (5 mL)and water (1 mL) was degassed with nitrogen and stirred at 80° C. for 1hour. After cooling to r.t., the reaction mixture was concentrated andthe crude residue was purified by silica gel flash column chromatography(eluting with a gradient of 0 to 50% EtOAc/hexanes). LCMS calculated forC₂₃H₂₃ClN₇O₃S (M+H)⁺: m/z=512.1; Found 512.2.

Intermediate 30.5-Formyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inIntermediate 23, using 2-fluoro-5-formylbenzonitrile instead of3-chloro-4-fluorobenzaldehyde as starting material. LCMS calculated forC₁₇H₁₉BN₃O₃ (M+H)⁺: m/z=324.2; Found: 324.1.

Intermediate 31. tert-Butyl4-((5-cyano-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of tert-butyl4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 13, 2.10 g, 6.22 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(2.74 g, 9.32 mmol), XPhos Pd G2 (0.245 g, 0.311 mmol), and potassiumphosphate, tribasic (5.28 g, 24.9 mmol) in 1,4-dioxane (12.95 mL) andwater (2.59 mL) was degassed with nitrogen and irradiated in a microwavereactor at 80° C. for 3 hours. The reaction temperature was thenincreased to 120° C. and microwave irradiation was continued for anadditional 2 hours. After cooling to r.t., the mixture was then dilutedwith EtOAc and extracted with saturated aqueous NaCl. The aqueous layerwas washed with EtOAc and the combined organic phases were then driedover MgSO₄ and concentrated. To the crude residue was then added CH₂Cl₂,followed by Et₂O and hexanes. The mixture was slurried for 30 minutes,and solid precipitate that formed was then collected via filtration,washed with hexanes, and dried under air. The crude material obtainedwas used directly without further purification. LCMS calculated forC₁₄H₁₆N₇O₂ (M+1-C₄H₈)⁺: m/z=314.1; Found: 314.1.

Intermediate 32.2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-4-(1H-pyrazol-4-yl)pyrimidine-5-carbonitrile

This compound was prepared according to the procedures described inIntermediate 31, using4-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Intermediate 26) instead of tert-butyl4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 13) as starting material. LCMS calculated for C₁₄H₁₈N₇O₂S(M+H)⁺: m/z=348.1; Found: 348.1.

Intermediate 33.4-(1-(6-Formyl-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

A mixture of2-((1-(methylsulfonyl)piperidin-4-yl)amino)-4-(1H-pyrazol-4-yl)pyrimidine-5-carbonitrile(Intermediate 32, 50.0 mg, 0.144 mmol), 5-fluoro-6-methylpicolinaldehyde(30.0 mg, 0.216 mmol), and potassium phosphate, tribasic (61.1 mg, 0.288mmol) in DMF (1 mL) was stirred at 100° C. for 1 hour. After cooling tor.t., the reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The crude residue was then purifiedby silica gel flash column chromatography (eluting with a gradient of 0to 10% MeOH/CH₂C₁₋₂). LCMS calculated for C₂₁H₂₃N₈O₃S (M+H)⁺: m/z=467.2;Found 467.0.

Intermediate 34. tert-Butyl4-((4-(1-(2-chloro-4-formylphenyl)-1H-pyrazol-4-yl)-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 33, using 3-chloro-4-fluorobenzaldehyde instead of5-fluoro-6-methylpicolinaldehyde and tert-butyl4-((5-cyano-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 31) instead of2-((1-(methylsulfonyl)piperidin-4-yl)amino)-4-(1H-pyrazol-4-yl)pyrimidine-5-carbonitrile(Intermediate 32) as starting materials. LCMS calculated forC₂₅H₂₇ClN₇O₃ (M+H)⁺: m/z=508.2; Found: 508.2.

Example 1.N-(1-((1-Methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture ofN-(piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2, 124 mg, 0.315 mmol) in THF (3 mL) was added1-methyl-1H-pyrazole-4-sulfonyl chloride (56.9 mg, 0.315 mmol) andtriethylamine (0.05 mL, 0.36 mmol) and the reaction mixture was stirredat r.t. for 10 minutes. The reaction was then quenched via the additionof water, and the mixture was diluted with acetonitrile and severaldrops of TFA and purified with prep-LCMS (Sunfire C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). LCMS calculated for C₁₉H₂₁F₆N₈O₂S (M+H)⁺: m/z=539.1;Found 539.1.

Example 2.N-(1-((1H-Pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 1, using 1H-pyrazole-4-sulfonyl chloride instead of1-methyl-1H-pyrazole-4-sulfonyl chloride as starting material. Purifiedwith prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₁₈H₁₉F₆N₈O₂S (M+H)⁺: m/z=525.1; Found 525.0.

Example 3.N-(1-(Methylsulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture ofN-(piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 3, 10 mg, 0.025 mmol) in THF (1 mL) was addedmethanesulfonyl chloride (5 mg, 0.044 mmol) and Hunig's base (8 mg, 0.06mmol) and the reaction mixture was stirred at r.t. for 10 minutes. Thereaction was then quenched via the addition of water, and the mixturewas diluted with acetonitrile and several drops of TFA and purified withprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₁₉H₂₆F₃N₆O₃S (M+H)⁺: m/z=475.2; Found 475.1.

Example 4.2-((4-((4-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)acetonitrile

This compound was prepared according to the procedures described inExample 3, using cyanomethanesulfonyl chloride instead ofmethanesulfonyl chloride as starting material. Purified with prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₀H₂₅F₃N₇O₃S (M+H)⁺: m/z=500.2; Found: 500.1.

Example 5.N-(1-(Benzylsulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 3, using phenylmethanesulfonyl chloride instead ofmethanesulfonyl chloride as starting material. Purified with prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₅H₃₀F₃N₆O₃S (M+H)⁺: m/z=551.2; Found: 551.2.

Example 6.4-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-N-(1-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 3, using tetrahydro-2H-pyran-4-sulfonyl chloride instead ofmethanesulfonyl chloride as starting material. Purified with prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₃H₃₂F₃N₆O₄S (M+H)⁺: m/z=545.2; Found: 545.2.

Example 7.3-((4-((4-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile

This compound was prepared according to the procedures described inExample 3, using 3-cyanobenzenesulfonyl chloride instead ofmethanesulfonyl chloride as starting material. Purified with prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TEA, at flow rate of 60 mL/min). LCMS calculated forC₂₅H₂₇F₃N₇O₃S (M+H)⁺: m/z=562.2; Found: 562.4.

Example 8.N-(4-((4-((4-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)morpholine-4-carboxamide

This compound was prepared according to the procedures described inExample 3, using 4-(morpholine-4-carboxamido)benzenesulfonyl chlorideinstead of methanesulfonyl chloride as starting material. Purified withprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₉H₃₆f₃N₈O₅S (M+H)⁺: m/z=665.2; Found: 665.3.

Example 9.N-(1-((1-Methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2/7-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 3, using 1-methyl-1H-pyrazole-4-sulfonyl chloride instead ofmethanesulfonyl chloride as starting material. Purified with prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TEA, at flow rate of 60 mL/min). LCMS calculated forC₂₂H₂₈F₃N₈O₃S (M+H)⁺: m/z=541.2; Found: 541.1.

Example 10.N-(1-(Methylsulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 4, 325 mg, 0.906 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole(375 mg, 1.36 mmol), Pd(dppf)Cl₂ DCM adduct (148 mg, 0.181 mmol), andsodium carbonate (192 mg, 1.81 mmol) in acetonitrile (5 mL) and water (1mL) was purged with nitrogen and irradiated in a microwave reactor at100° C. for 30 minutes. The obtained crude product was purified byBiotage Isolera™ Fractions containing the desired product were thenconcentrated, and the material obtained was dissolved in acetonitrileand purified with prep-LCMS (Sunfire C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LCMS calculated for C₁₆H₁₉F₆N₆O₂S (M+H)⁺: m/z=473.1; Found 473.1.

Example 11.4-(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 10, using1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidineinstead of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazoleas starting material. Purified with prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₀H₂₉F₃N₇O₂S (M+H)⁺:m/z=488.2; Found: 488.2. ¹H NMR (500 MHz, DMSO-D₆) δ 8.60 (s, 1H), 8.26(s, 1H), 8.05 (s, 1H), 7.82 (s, 1H), 4.66 (s, 1H), 4.13-4.01 (m, 1H),3.70-3.56 (m, 4H), 3.27-3.12 (m, 2H), 3.02-2.94 (m, 2H), 2.92 (s, 3H),2.90 (s, 3H), 2.40-2.19 (m, 4H), 2.08-1.98 (m, 2H), 1.74-1.63 (m, 2H).

Example 12.4-(1-Cyclohexyl-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 4, 50 mg, 0.14 mmol),1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(58 mg, 0.21 mmol), Pd(dppf)Cl₂ DCM adduct (22.8 mg, 0.028 mmol), andsodium carbonate (29.5 mg, 0.28 mmol) in acetonitrile (2 mL) and water(0.4 mL) was purged under nitrogen and irradiated in a microwave reactorat 100° C. for 30 minutes. After cooling to r.t., the crude mixture wasthen diluted with water and several drops of TFA and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).The fractions containing product were then concentrated and purifiedwith prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₀H₂₈F₃N₆O₂S (M+H)⁺: m/z=473.2; Found 473.3.

Example 13.4-(1-(2-Fluorophenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 12, using (1-(2-fluorophenyl)-1H-pyrazol-4-yl)boronic acidinstead of1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas starting material. Purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% NH₄OH, atflow rate of 60 mL/min). The fractions containing product were thenconcentrated and purified with prep-LCMS (Sunfire C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). LCMS calculated for C₂₀H₂₁F₄N₆O₂S (M+H)⁺: m/z=485.1;Found: 485.2.

Example 14.4-(1-(2-Chlorophenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 12, using (1-(2-chlorophenyl)-1H-pyrazol-4-yl)boronic acidinstead of1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas starting material. Purified with prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TEA, atflow rate of 60 mL/min). The fractions containing product were thenconcentrated and purified with prep-LCMS (Sunfire C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). LCMS calculated for C₂₀H₂₁ClF₃N₆O₂S (M+H)⁺: m/z=501.1;Found: 501.2.

Example 15.5-Fluoro-4-(3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine

Step 1: tert-Butyl4-(4-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.299 mmol),tert-butyl4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(117 mg, 0.299 mmol), sodium carbonate (63.5 mg, 0.599 mmol), andPd(dppf)Cl₂ DCM adduct (24.5 mg, 0.030 mmol) in acetonitrile (2.5 mL)and water (0.5 mL) was purged with nitrogen and irradiated at 100° C. ina microwave reactor for 15 minutes. After cooling to r.t., the reactionmixture was then diluted with water and extracted with CH₂Cl₂. Thecombined organic phases were then filtered over a phase separator andconcentrated. The crude material obtained was used without furtherpurification. LCMS calculated for C₁₈H₂₄ClFN₅O₂ (M+H)⁺: m/z=396.2; Found396.2.

Step 2:5-Fluoro-4-(3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine

A mixture of tert-butyl4-(4-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate(from step 1), 1-(methylsulfonyl)piperidin-4-amine (53.4 mg, 0.299mmol), RuPhos Pd G3 (25 mg, 0.030 mmol), cesium carbonate (195 mg, 0.599mmol), and 1,4-dioxane (2 mL) was purged with nitrogen and irradiated inthe microwave at 140° C. for 30 minutes. After cooling to r.t., thereaction mixture was filtered over a pad of celite and concentrated.Then, a 4 molar solution of HCl in 1,4-dioxane (3 mL) was added to thecrude residue and the mixture was stirred at r.t. for 2 hours. The crudemixture was then diluted with water (10 mL) and the aqueous layer wasextracted with CH₂Cl₂. The organic layer was removed and the aqueouslayer was made basic via the addition of a 50% aqueous solution of NaOH.The aqueous layer was then extracted with EtOAc and CH₂Cl₂ and thecombined organic phases were dried over MgSO₄ and concentrated. Thecrude material obtained was used without further purification. LCMScalculated for C₁₉H₂₉FN₇O₂S (M+H)⁺: m/z=438.2; Found 438.2.

Step 3:5-Fluoro-4-(3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine

To a mixture of5-fluoro-4-(3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine(from step 2) in THF (1 mL) was added a 37 wt % aqueous solution offormaldehyde (0.07 mL, 0.940 mmol) followed by acetic acid (0.05 mL,0.873 mmol) and sodium triacetoxyborohydride (127 mg, 0.599 mmol) andthe reaction mixture was stirred at r.t. for 2 hours. The reactionmixture was then diluted with water, acetonitrile, and several drops ofTFA and purified with prep-LCMS (Sunfire C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₀H₃₁FN₇O₂S (M+H)⁺: m/z=452.2; Found452.2.

Example 16.4-(3-Methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 15, using 2,4-dichloropyrimidine instead of2,4-dichloro-5-fluoropyrimidine as starting material. Purified withprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₀H₃₂N₇O₂S (M+H)⁺: m/z=434.2; Found: 434.2.

Example 17.5-Fluoro-4-(1-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 15, using tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate 5) instead of tert-butyl4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateas starting material. Purified with prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₀H₂₈F₄N₇O₂S (M+H)⁺:m/z=506.2; Found: 506.2.

Example 18.4-(1-(1-Methylpiperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:N-(1-(Methylsulfonyl)piperidin-4-yl)-4-(1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 4, 54 mg, 0.15 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate 6, 67 mg, 0.15 mmol), Pd(PPh₃)₂Cl₂ (21.1 mg, 0.030 mmol),and sodium carbonate (31.9 mg, 0.301 mmol) in 1,4-dioxane (1 mL) andwater (0.2 mL) was purged with nitrogen and irradiated in a microwavereactor at 100° C. for 30 minutes. After cooling to r.t., the reactionmixture was filtered over a pad of MgSO₄ and concentrated. Then, a 4molar solution of HCl in 1,4-dioxane (3 mL) was added to the cruderesidue and the mixture was stirred at r.t. for 2 hours. The crudemixture was then diluted with water (10 mL) and the aqueous layer wasextracted with CH₂Cl₂. The organic layer was removed and the aqueouslayer was made basic via the addition of a 50% aqueous solution of NaOH.The aqueous layer was then extracted with EtOAc and CH₂Cl₂ and thecombined organic phases were dried over MgSO₄ and concentrated. LCMScalculated for C₂₀H₂₆F₆N₇O₂S (M+H)⁺: m/z=542.2; Found 542.2.

Step 2:4-(1-(1-Methylpiperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture ofN-(1-(methylsulfonyl)piperidin-4-yl)-4-(1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(from step 1) in THF (2 mL) was added a 37 wt % aqueous solution offormaldehyde (0.04 mL, 0.54 mmol) followed by acetic acid (0.04 mL, 0.70mmol) and sodium triacetoxyborohydride (63.8 mg, 0.301 mmol) and thereaction mixture was stirred at r.t. for 2 hours. The reaction mixturewas then diluted with water, acetonitrile, and several drops of TFA andpurified with prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₁H₂₈F₆N₇O₂S (M+H)⁺: m/z=556.2; Found 556.2.

Example 19.(±)-N-(1-(Methylsulfonyl)piperidin-3-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of2-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine(Intermediate 7, 25 mg, 0.075 mmol),(±)-1-methanesulfonylpiperidin-3-amine (20.1 mg, 0.113 mmol), RuPhos PdG2 (11.7 mg, 0.015 mmol), and cesium carbonate (49.0 mg, 0.150 mmol) in1,4-dioxane (1.0 mL) was purged under nitrogen at r.t. before heating to100° C. overnight. After cooling to r.t., the crude mixture was thendiluted with water and several drops of TFA and purified with prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). The fractionscontaining product were then concentrated and purified with prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₁₉H₂₆F₃N₆O₃S (M+H)⁺: m/z=475.2; Found 475.1.

Example 20.N-(1-(Methylsulfonyl)azetidin-3-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of2-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine(Intermediate 7, 25 mg, 0.075 mmol), tert-butyl3-aminoazetidine-1-carboxylate (19.4 mg, 0.113 mmol), RuPhos Pd G2 (11.7mg, 0.015 mmol), and cesium carbonate (49.0 mg, 0.150 mmol) in1,4-dioxane (1.0 mL) was purged under nitrogen at r.t. before heating to100° C. overnight. After cooling to r.t., a 4 molar solution of HCl in1,4-dioxane (500 μL) was added to the crude residue and the mixture wasstirred at r.t. for 2 hours. The reaction mixture was then concentratedunder reduced pressure and redissolved in CH₂Cl₂. MsCl (30.0 μL, 0.385mmol) and Et₃N (500 μL, 3.59 mmol) were then added and the reactionmixture was stirred at r.t. for 10 min. The crude mixture was thendiluted with water and several drops of TFA and purified with prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₁₇H₂₂F₃N₆O₃S (M+H)⁺: m/z=447.1; Found 447.2.

Example 21.(±)-N-((2S,4R)-2-Methyl-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 20, using (±)-tert-butyl (2R,4R)-4-amino-2-methylpiperidine-1-carboxylate hydrochloride instead of tert-butyl3-aminoazetidine-1-carboxylate as starting material and an additionalequivalent of cesium carbonate. The crude mixture was diluted with waterand several drops of TFA and purified with prep-LCMS (Sunfire C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The fractions containing product werethen concentrated and purified with prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₀H₂₈F₃N₆O₃S (M+H)⁺:m/z=489.2; Found: 489.2.

Example 22.5-Chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine

A mixture of2,5-dichloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidine(Intermediate 8, 20 mg, 0.067 mmol), 1-(methylsulfonyl)piperidin-4-amine(17.9 mg, 0.100 mmol) and cesium carbonate (45.7 mg, 0.140 mmol) in1,4-dioxane (0.7 mL) was degassed with nitrogen before RuPhos Pd G2 (5.2mg, 6.7 μmol) was added and the mixture was degassed with nitrogen foran additional 2 minutes. The reaction mixture was then sealed andstirred at 100° C. for 2 hours. After cooling to r.t., the reactionmixture was diluted with methanol and purified with prep-LCMS (SunfireC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C₁₈H₂₆ClN₆O₃S(M+H)⁺: m/z=441.1; Found: 441.1.

Example 23.N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture ofN-(piperidin-4-yl)-4-(1-(tetrahydro-2F7-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 3, 50 mg, 0.126 mmol) and N,N-diisopropylethylamine(Hunig's base) (88 μL, 0.505 mmol) in acetonitrile (2 mL) was added1-methyl-1H-imidazole-4-sulfonyl chloride (34.2 mg, 0.189 mmol) and thereaction mixture was stirred at r.t. overnight. The reaction mixture wasthen diluted with methanol, water, and the mixture was adjusted to pH≤2using trifluoroacetic acid (TFA) and purified with prep-LCMS (SunfireC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₂H₂₈F₃N₈O₃S(M+H)⁺: m/z=541.2; Found 541.2. ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (d,J=18.7 Hz, 1H), 8.23 (d, J=24.5 Hz, 1H), 8.01-7.79 (m, 4H), 4.60-4.47(m, 1H), 3.97 (d, J=11.4 Hz, 2H), 3.92-3.76 (m, 1H), 3.73 (s, 3H), 3.58(dt, J=12.4, 3.8 Hz, 2H), 3.46 (td, J=11.4, 3.5 Hz, 2H), 2.71 (t, J=11.7Hz, 1H), 2.68-2.59 (m, 1H), 2.05-1.84 (m, 6H), 1.57 (qd, J=11.7, 3.9 Hz,2H). Corrected due to presence of rotamers: ¹H NMR (500 MHz, DMSO-d₆)(mixture of rotamers) δ 8.54 (s, 0.4H), 8.51 (s, 0.6H), 8.26 (s, 0.6H),8.21 (s, 0.4H), 7.98 (s, 0.6H), 7.95-7.87 (m, 1.4H), 7.84 (s, 1H), 7.81(s, 1H), 4.60-4.47 (m, 1H), 3.97 (d, J=11.4 Hz, 2H), 3.92-3.76 (m, 1H),3.73 (s, 3H), 3.64-3.53 (m, 2H), 3.46 (td, J=11.4, 3.5 Hz, 2H), 2.71 (t,J=11.7 Hz, 1H), 2.68-2.59 (m, 1H), 2.05-1.84 (m, 6H), 1.57 (qd, J=11.7,3.9 Hz, 2H).

Example 24.N-(1-((1-Ethyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to a modification of the proceduresdescribed in Example 23, using 1-ethyl-1H-imidazole-4-sulfonyl chloride(1.2 equiv) instead of 1-methyl-1H-imidazole-4-sulfonyl chloride asstarting material. Purified with prep-LCMS (Sunfire C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). LCMS calculated for C₂₃H₃₀F₃N₈O₃S (M+H)⁺: m/z=555.2;Found 555.4. ¹H NMR (500 MHz, DMSO-d₆) δ 8.52 (d, J=15.6 Hz, 1H), 8.22(d, J=19.5 Hz, 1H), 8.03-7.81 (m, 4H), 4.59-4.48 (m, 1H), 4.07 (q, J=7.3Hz, 2H), 4.01-3.93 (m, 2H), 3.85 (d, J=29.7 Hz, 1H), 3.60 (dt, J=12.2,4.0 Hz, 2H), 3.52-3.40 (m, 2H), 2.80-2.60 (m, 2H), 2.05-1.85 (m, 6H),1.58 (qd, J=11.5, 4.0 Hz, 2H), 1.39 (t, J=7.3 Hz, 3H). Corrected due topresence of rotamers: ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ8.54 (s, 0.4H), 8.51 (s, 0.6H), 8.24 (s, 0.6H), 8.20 (s, 0.4H), 7.97 (s,0.6H), 7.90 (s, 1.4H), 7.88 (s, 1H), 7.85 (d, J=7.5 Hz, 1H), 4.59-4.48(m, 1H), 4.07 (q, J=7.3 Hz, 2H), 4.01-3.93 (m, 2H), 3.93-3.76 (m, 1H),3.60 (dt, J=12.2, 4.0 Hz, 2H), 3.52-3.40 (m, 2H), 2.80-2.60 (m, 2H),2.05-1.85 (m, 6H), 1.58 (qd, J=11.5, 4.0 Hz, 2H), 1.39 (t, J=7.3 Hz,3H).

Example 25.N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:N-(Piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a microwave vial with a stir bar, a mixture of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 7, 3.00 g, 7.88 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole(2.61 g, 9.45 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (Pd(dppf)Cl₂ CH₂Cl₂ adduct) (0.643 g, 0.788 mmol),and sodium carbonate (5.01 g, 47.3 mmol) in acetonitrile (16 mL) andwater (3.2 mL) was sparged with nitrogen and irradiated in a microwavereactor at 110° C. for 2 hours. After cooling to r.t., a 4 molarsolution of HCl in 1,4-dioxane (24 mL, 96 mmol) was added and thereaction mixture was stirred at r.t. overnight. The mixture was thendiluted with water and extracted with CH₂Cl₂. The organic layer wasdiscarded and the aqueous layer was made basic via the addition of a 50%aqueous solution of NaOH and extracted with EtOAc and CH₂Cl₂. Thecombined organic phases were then washed with brine, dried over MgSO₄,and concentrated. The crude material obtained was then used directlywithout further purification. LCMS calculated for C₁₅H₁₇F₆N₆ (M+H)⁺:m/z=395.1; Found 395.3.

Step 2:N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture ofN-(piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(from Step 1) in THF (20 mL) was added 1-methyl-1H-imidazole-4-sulfonylchloride (1.42 g, 7.86 mmol) followed by dropwise addition oftriethylamine (1.1 mL, 7.88 mmol), and the reaction mixture was stirredat r.t. for 1 hour. The reaction mixture was then concentrated in vacuo,and to the crude residue was added acetonitrile, water, and TFA (0.6mL), and was purified with prep-LCMS (Sunfire C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₁₉H₂₁F₆N₈O₂S (M+H)⁺: m/z=539.1; Found539.1. ¹H NMR (500 MHz, DMSO-d₆) δ 8.56 (d, J=17.3 Hz, 1H), 8.36 (d,J=28.5 Hz, 1H), 8.05 (d, J=50.5 Hz, 2H), 7.98 (d, J=9.3 Hz, 1H), 7.83(s, 1H), 7.81 (d, J=1.4 Hz, 1H), 5.27 (q, J=9.0 Hz, 2H), 3.93-3.76 (m,1H), 3.72 (s, 3H), 3.63-3.53 (m, 2H), 2.76-2.58 (m, 2H), 2.02-1.85 (m,2H), 1.57 (q, J=11.6 Hz, 2H). Corrected due to presence of rotamers: ¹HNMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.58 (s, 0.4H), 8.54 (s,0.6H), 8.38 (s, 0.6H), 8.33 (s, 0.4H), 8.15-7.94 (m, 2H), 7.85-7.79 (m,2H), 5.27 (q, J=9.0 Hz, 2H), 3.93-3.76 (m, 1H), 3.72 (s, 3H), 3.63-3.53(m, 2H), 2.76-2.58 (m, 2H), 2.02-1.85 (m, 2H), 1.64-1.51 (m, 2H).

Example 26.trans-4-(4-(2-((1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol

Step 1:trans-4-(4-(2-(Piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol

In a microwave vial with a stir bar, a mixture of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 1, 300 mg, 0.788 mmol),trans-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol(384 mg, 0.945 mmol), Pd(dppf)Cl₂ CH₂Cl₂ adduct (64.3 mg, 0.079 mmol),and sodium carbonate (501 mg, 4.73 mmol) in acetonitrile (3.28 mL) andwater (0.657 mL) was sparged with nitrogen and irradiated in a microwavereactor at 110° C. for 2 hours. After cooling to r.t., a 4 molarsolution of HCl in 1,4-dioxane (2.5 mL, 10.0 mmol) was added and thereaction mixture was stirred at r.t. for 4 hours. The mixture was thendiluted with water and extracted with CH₂Cl₂. The organic layer wasdiscarded and the aqueous layer was made basic via the addition of a 50%aqueous solution of NaOH and extracted with EtOAc and CH₂Cl₂. Thecombined organic phases were then washed with brine, dried over MgSO₄,and concentrated. The crude material obtained was then used directlywithout further purification. LCMS calculated for C₁₉H₂₆F₃N₆O (M+H)⁺:m/z=411.2; Found 411.2.

Step 2:trans-4-(4-(2-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol

To a mixture oftrans-4-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol(315.3 mg, 0.601 mmol) in THF (5 mL) was added1-methyl-1H-imidazole-4-sulfonyl chloride (108 mg, 0.599 mmol) followedby dropwise addition of triethylamine (0.165 mL, 1.18 mmol) and thereaction mixture was stirred at r.t. for 1 hour. The reaction mixturewas then concentrated in vacuo, and to the crude residue was addedacetonitrile, water, and several drops of TFA, and the mixture waspurified with prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₃H₃₀F₃N₈O₃S (M+H)⁺: m/z=555.2; Found 555.2. ¹H NMR (500MHz, DMSO-d₆) δ 8.52 (d, J=19.2 Hz, 1H), 8.19 (d, J=23.3 Hz, 1H),7.96-7.85 (m, 2H), 7.85-7.78 (m, 2H), 4.31-4.19 (m, 1H), 3.92-3.75 (m,1H), 3.73 (s, 3H), 3.58 (dt, J=11.9, 4.0 Hz, 2H), 3.54-3.45 (m, 1H),2.76-2.59 (m, 2H), 2.03-1.87 (m, 6H), 1.87-1.73 (m, 2H), 1.57 (qd,J=11.6, 4.0 Hz, 2H), 1.34 (dt, J=13.2, 9.8 Hz, 2H). Corrected due topresence of rotamers: ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ8.53 (s, 0.4H), 8.50 (s, 0.6H), 8.21 (s, 0.6H), 8.16 (s, 0.4H),7.96-7.85 (m, 2H), 7.85-7.78 (m, 2H), 4.31-4.19 (m, 1H), 3.92-3.75 (m,1H), 3.73 (s, 3H), 3.58 (dt, J=11.9, 4.0 Hz, 2H), 3.54-3.45 (m, 1H),2.76-2.59 (m, 2H), 2.03-1.87 (m, 6H), 1.87-1.73 (m, 2H), 1.57 (qd,j=11.6, 4.0 Hz, 2H), 1.34 (dt, J=13.2, 9.8 Hz, 2H).

Example 27.3-Chloro-4-(4-(2-(1-(methylsulfonyl)piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzonitrile

A mixture ofN-(1-(methylsulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 9, 600 mg, 1.54 mmol), 3-chloro-4-fluorobenzonitrile (598mg, 3.84 mmol), and potassium phosphate, tribasic (1.31 g, 6.15 mmol) inDMSO (4.0 mL) was heated to 140° C. for 30 minutes. After cooling tor.t., the reaction mixture was diluted with water and extracted withEtOAc. The combined organic phases were then dried over MgSO₄,concentrated under reduced pressure, and purified via flash columnchromatography (Agela Flash Column Silica-CS (40 g), eluting with agradient of 0 to 50% EtOAc/CH₂C₁₋₂). Fractions containing the desiredproduct were then concentrated, and the material obtained was purifiedwith prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₁H₂₀ClF₃N₇O₂S (M+H)⁺: m/z=526.1; Found: 526.0. ¹H NMR(400 MHz, DMSO-d₆) δ 8.82-8.52 (m, 2H), 8.44-8.37 (d, 1H), 8.37-8.20 (d,J=66.7 Hz, 1H), 8.15-8.07 (d, J=7.8 Hz, 1H), 8.07-8.02 (t, J=6.7 Hz,1H), 7.95-7.87 (dd, J=13.2, 8.2 Hz, 1H), 4.19-3.88 (m, 1H), 3.61-3.48(dd, J=11.9, 3.4 Hz, 2H), 3.00-2.80 (m, 5H), 2.06-1.89 (m, 2H),1.67-1.53 (m, 2H). ¹⁹F NMR (376 MHz, DMSO) δ −56.46-−58.01 (d, J=134.2Hz). Corrected due to presence of rotamers: ¹H NMR (600 MHz, DMSO-d₆)(mixture of rotamers) δ 8.75 (s, 0.6H), 8.67 (s, 0.8H), 8.61 (s, 0.6H),8.41-8.37 (m, 1H), 8.34 (s, 0.6H), 8.23 (s, 0.4H), 8.10 (d, J=7.7 Hz,1H), 8.07-8.02 (m, 1H), 7.95-7.88 (m, 1H), 4.10-3.93 (m, 1H), 3.59-3.52(m, 2H), 2.97-2.82 (m, 5H), 2.05-1.93 (m, 2H), 1.65-1.54 (m, 2H). ¹⁹FNMR (376 MHz, DMSO) δ −57.0 (s, 1.3F), −57.3 (s, 1.7F).

Example 28.N-(cis-3-Hydroxy-1-methylcyclobutyl)-6-methyl-5-(4-(2-(1-(methylsulfonyl)piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)picolinamide

This compound was prepared according to a modification of the proceduresdescribed in Example 27, usingN-(cis-3-(tert-butyldimethylsilyloxy)-1-methylcyclobutyl)-5-fluoro-6-methylpicolinamide(Intermediate 10) instead of 3-chloro-4-fluorobenzonitrile as startingmaterial. After the reaction mixture was cooled to r.t., the crudemixture was treated with a 1 molar solution of tetrabutyl ammoniumfluoride (TBAF) in THE to remove the tert-butyldimethylsilyl (TBS)protecting group. The crude material was first purified via flash columnchromatography (Agela Flash Column Silica-CS, eluting with a gradient of0 to 15% MeOH/CH₂C₁₋₂), then purified with prep-LCMS (Sunfire C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₆H₃₂F₃N₈O₄S(M+H)⁺: m/z=609.2; Found 609.2. ¹H NMR (600 MHz, DMSO-d₆) δ 8.72-8.50(m, 3H), 8.33-8.17 (d, J=64.0 Hz, 1H), 8.11-7.95 (m, 3H), 4.12-3.93 (m,2H), 3.65-3.44 (d, J=3.8 Hz, 2H), 3.00-2.82 (m, 5H), 2.60-2.53 (d, J=8.5Hz, 3H), 2.49-2.45 (d, J=3.3 Hz, 2H), 2.26-2.07 (m, 2H), 2.06-1.92 (dd,0.7=22.6, 13.2 Hz, 2H), 1.67-1.55 (m, 2H), 1.45-1.35 (s, 3H). Correcteddue to presence of rotamers: ¹H NMR (600 MHz, DMSO-d₆) (mixture ofrotamers) δ 8.67 (s, 1.4H), 8.66 (s, 0.6H), 8.61 (s, 0.6H), 8.56 (s,0.4H), 8.31 (s, 0.6H), 8.20 (s, 0.4H), 8.11-8.04 (m, 2H), 8.02-7.98 (m,1H), 4.10-3.95 (m, 2H), 3.59-3.52 (m, 2H), 2.97-2.84 (m, 5H), 2.56 (s,1.8H), 2.55 (s, 1.2H), 2.53-2.46 (m, 2H), 2.17-2.11 (m, 2H), 2.05-1.94(m, 2H), 1.65-1.55 (m, 2H), 1.41 (s, 3H).

Example 29.4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-V-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture ofN-(1-(methylsulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 9, 100 mg, 0.256 mmol), 3-chloro-4-fluorobenzaldehyde (122mg, 0.768 mmol), and potassium phosphate, tribasic (217 mg, 1.025 mmol)in DMSO (500 μL) was heated to 140° C. for 30 minutes. After cooling tor.t., the reaction mixture was diluted with 1 molar HCl and extractedwith EtOAc. The combined organic phases were then dried over MgSO₄ andconcentrated under reduced pressure. To the crude residue was addedtoluene (500 μL) and acetic acid (500 μL), followed by a 2 molarsolution of methanamine in THF (900 μL) and the reaction mixture wasstirred at r.t. for 1 hour. The reaction mixture was then concentratedin vacuo, and to the crude residue was added 1,2-dichloroethane (500 μL)before sodium triacetoxy borohydride (543 mg, 2.56 mmol) was addedportion-wise followed by a drop of methanol, and the reaction mixturewas stirred at r.t. overnight. The mixture was then diluted with water,acetonitrile, and several drops of TEA and purified with prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₂H₂₆ClF₃N₇O₂S (M+H)⁺: m/z=544.2; Found: 544.4. ¹H NMR (600 MHz,DMSO-d₆) δ 8.92-8.89 (s, 2H), 8.68-8.61 (d, J=29.5 Hz, 1H), 8.61-8.52(d, J=43.2 Hz, 1H), 8.32-8.17 (d, 0.7=65.3 Hz, 1H), 8.11-8.04 (dd,J=16.4, 7.7 Hz, 1H), 7.89-7.85 (t, 0.7=2.1 Hz, 1H), 7.83-7.77 (dd,J=11.7, 8.2 Hz, 1H), 7.66-7.61 (d, J=8.2 Hz, 1H), 4.27-4.22 (s, 2H),4.15-3.94 (m, 1H), 3.59-3.53 (dd, J=11.7, 5.5 Hz, 2H), 2.97-2.84 (m,5H), 2.64-2.59 (t, J=5.1 Hz, 3H), 2.04-1.94 (m, 2H), 1.65-1.55 (m, 2H).¹⁹F NMR (565 MHz, DMSO) δ −56.77-−58.67 (d, J=197.4 Hz). Corrected dueto presence of rotamers: ¹H NMR (600 MHz, DMSO-d₆) (mixture of rotamers)δ 8.90 (s, 2H), 8.67 (s, 0.4H), 8.62 (s, 0.6H), 8.61 (s, 0.6H), 8.54 (s,0.4H), 8.30 (s, 0.6H), 8.19 (s, 0.4H), 8.11-8.04 (m, 1H), 7.89-7.85 (m,1H), 7.83-7.77 (m, 1H), 7.66-7.61 (m, 1H), 4.27-4.22 (m, 2H), 4.09-3.95(m, 1H), 3.60-3.52 (m, 2H), 2.97-2.83 (m, 5H), 2.62 (t, J=5.2 Hz, 3H),2.04-1.94 (m, 2H), 1.65-1.56 (m, 2H). ¹⁹F NMR (565 MHz, DMSO-d₆) δ −57.0(s, 1.3F), −57.4 (s, 1.7F).

Example 30.2-Methyl-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanamide

A mixture ofN-(1-(methylsulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 9, 10 mg, 0.026 mmol), 2-bromo-2-methylpropanamide (12.8mg, 0.077 mmol), and cesium carbonate (25.0 mg, 0.077 mmol) inacetonitrile (0.15 mL) was stirred at 80° C. for 2 hours. After coolingto r.t., the reaction mixture was diluted with methanol and purifiedwith prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₁₈H₂₅F₃N₇O₃S (M+H)⁺: m/z=476.2; Found: 476.2. ¹H NMR(500 MHz, DMSO-d₆) δ 8.57 (d, J=26.7 Hz, 1H), 8.22 (d, J=28.6 Hz, 1H),8.07-7.90 (m, 2H), 7.28 (s, 1H), 7.14 (s, 1H), 4.08-3.90 (m, 1H), 3.55(d, J=11.2 Hz, 2H), 3.01-2.80 (m, 5H), 2.06-1.90 (m, 2H), 1.75 (s, 3H),1.74 (s, 3H), 1.64-1.53 (m, 2H). Corrected due to presence of rotamers:¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.60 (s, 0.5H), 8.55(s, 0.5H), 8.25 (s, 0.5H), 8.20 (s, 0.5H), 8.07-7.90 (m, 2H), 7.28 (s,1H), 7.14 (s, 1H), 4.08-3.90 (m, 1H), 3.60-3.50 (m, 2H), 3.01-2.80 (m,5H), 2.06-1.90 (m, 2H), 1.75 (s, 3H), 1.74 (s, 3H), 1.64-1.53 (m, 2H).

Example 31.4-(1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture ofN-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 12, 10 mg, 0.022 mmol), 1,1-difluoro-2-iodoethane (12.6mg, 0.066 mmol), and cesium carbonate (21.4 mg, 0.066 mmol) inacetonitrile (0.15 mL) was stirred at 80° C. for 2 hours. After coolingto r.t., the reaction mixture was diluted with methanol and purifiedwith prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₁₉H₂₂F₅N₈O₂S (M+H)⁺: m/z=521.2; Found: 521.2. ¹H NMR(600 MHz, DMSO-d₆) δ 8.55 (d, J=20.8 Hz, 1H), 8.29 (d, J=38.9 Hz, 1H),8.07-7.93 (m, 2H), 7.84 (s, 1H), 7.81 (s, 1H), 6.40 (tt, J=54.8, 3.7 Hz,1H), 4.75 (td, J=15.1, 3.7 Hz, 2H), 3.97-3.77 (m, 1H), 3.72 (s, 3H),3.58 (d, J=11.8 Hz, 2H), 2.74-2.60 (m, 2H), 2.02-1.83 (m, 2H), 1.66-1.49(m, 2H). Corrected due to presence of rotamers: ¹H NMR (600 MHz,DMSO-d₆) (mixture of rotamers) δ 8.56 (s, 0.5H), 8.53 (s, 0.5H), 8.33(s, 0.5H), 8.26 (s, 0.5H), 8.07-7.93 (m, 2H), 7.84 (s, 1H), 7.81 (s,1H), 6.40 (tt, J=54.8, 3.7 Hz, 1H), 4.79-4.71 (m, 2H), 3.97-3.77 (m,1H), 3.72 (s, 3H), 3.61-3.54 (m, 2H), 2.74-2.60 (m, 2H), 2.02-1.83 (m,2H), 1.66-1.49 (m, 2H).

Example 32.4-(1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 31, using (bromomethyl)cyclopropane instead of1,1-difluoro-2-iodoethane as starting material. Purified with prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TEA, at flow rate of 60 mL/min). LCMS calculated forC₂₁H₂₆F₃N₈O₂S (M+H)⁺: m/z=511.2; Found: 511.2. ¹H NMR (500 MHz, DMSO-d₆)δ 8.52 (d, J=17.2 Hz, 1H), 8.24 (d, J=25.0 Hz, 1H), 8.01-7.78 (m, 4H),4.05 (d, J=7.1 Hz, 2H), 3.90-3.77 (m, 1H), 3.73 (s, 3H), 3.59 (d, J=11.9Hz, 2H), 2.83-2.57 (m, 2H), 2.02-1.85 (m, 2H), 1.65-1.51 (m, 2H),1.30-1.19 (m, 1H), 0.57-0.50 (m, 2H), 0.40-0.35 (m, 2H). Corrected dueto presence of rotamers: ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers)δ 8.54 (s, 0.5H), 8.51 (s, 0.5H), 8.27 (s, 0.5H), 8.22 (s, 0.5H),7.97-7.87 (m, 2H), 7.84 (s, 1H), 7.81 (s, 1H), 4.05 (d, J=7.1 Hz, 2H),3.90-3.77 (m, 1H), 3.73 (s, 3H), 3.62-3.54 (m, 2H), 2.83-2.57 (m, 2H),2.02-1.85 (m, 2H), 1.65-1.51 (m, 2H), 1.30-1.19 (m, 1H), 0.57-0.50 (m,2H), 0.40-0.35 (m, 2H).

Example 33.(R)—N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture ofN-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 72, 10 mg, 0.022 mmol), (R)-(tetrahydrofuran-3-yl)methanol(6.7 mg, 0.066 mmol), and triphenylphosphine (20.1 mg, 0.077 mmol) inTHF (0.15 mL) was heated to 80° C. At this temperature, diisopropylazodicarboxylate (8.5 μL, 0.044 mmol) in THF (0.110 mL) was added dropwise, and the reaction mixture was stirred at 80° C. for 1 hour. Aftercooling to r.t., the reaction mixture was diluted with methanol andpurified with prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₂H₂₈F₃N₈O₃S (M+H)⁺: m/z=541.2; Found: 541.2. ¹H NMR(500 MHz, DMSO-d₆) δ 8.53 (d, J=18.7 Hz, 1H), 8.25 (d, J=38.5 Hz, 1H),8.00-7.88 (m, 2H), 7.84 (s, 1H), 7.82 (s, 1H), 4.25-4.15 (m, 2H),3.92-3.70 (m, 5H), 3.69-3.54 (m, 4H), 3.50-3.42 (m, 1H), 2.81-2.57 (m,3H), 1.99-1.83 (m, 3H), 1.64-1.51 (m, 3H). Corrected due to presence ofrotamers: ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.54 (s,0.5H), 8.51 (s, 0.5H), 8.29 (s, 0.5H), 8.21 (s, 0.5H), 8.00-7.88 (m,2H), 7.84 (s, 1H), 7.82 (s, 1H), 4.25-4.15 (m, 2H), 3.92-3.70 (m, 5H),3.69-3.54 (m, 4H), 3.50-3.42 (m, 1H), 2.81-2.57 (m, 3H), 1.99-1.83 (m,3H), 1.64-1.51 (m, 3H).

Example 34.trans-4-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclohexane-1-carbonitrile

To a mixture ofN-(1-(methylsulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 9, 250 mg, 0.640 mmol),4-hydroxycyclohexane-1-carbonitrile (240 mg, 1.92 mmol), and triphenylphosphine (336 mg, 1.28 mmol) in THF (3.2 mL) was added di-tert-butyl(E)-diazene-1,2-dicarboxylate (442 mg, 1.92 mmol) and the reactionmixture was purged with nitrogen and irradiated in a microwave reactorat 130° C. for 1 hour. After cooling to r.t., the mixture was dilutedwith acetonitrile, water, and several drops of TFA, and the mixture waspurified with prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). Thesecond peak was collected, and the material obtained was furtherpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calculated for C₂₁H₂₇F₃N₇O₂S (M+H)⁺: m/z=498.1; Found: 498.1. ¹HNMR (500 MHz, DMSO-d₆) δ 8.56 (d, J=29.4 Hz, 1H), 8.19 (d, J=19.8 Hz,1H), 8.06-7.86 (m, 2H), 4.42-4.29 (m, 1H), 4.07-3.91 (m, 1H), 3.60-3.50(m, 2H), 3.00-2.75 (m, 6H), 2.20-2.11 (d, J=12.3 Hz, 2H), 2.10-2.02 (m,2H), 2.02-1.90 (m, 2H), 1.90-1.76 (m, 2H), 1.76-1.65 (m, 2H), 1.65-1.53(m, 2H). Corrected due to presence of rotamers: ¹H NMR (500 MHz,DMSO-d₆) (mixture of rotamers) δ 8.59 (s, 0.5H), 8.53 (s, 0.5H), 8.21(s, 0.5H), 8.17 (s, 0.5H), 8.01 (s, 0.5H), 7.98-7.86 (m, 1.5H),4.42-4.29 (m, 1H), 4.07-3.91 (m, 1H), 3.60-3.50 (m, 2H), 3.00-2.75 (m,6H), 2.20-2.11 (m, 2H), 2.10-2.02 (m, 2H), 2.02-1.90 (m, 2H), 1.90-1.76(m, 2H), 1.76-1.65 (m, 2H), 1.65-1.53 (m, 2H).

Example 35.4-(1-(2-Amino-3-methylpyridin-4-yl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of 4-chloro-3-methylpyridin-2-amine (37.5 mg, 0.263 mmol),N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 72, 40 mg, 0.088 mmol), and cesium carbonate (114 mg,0.351 mmol) in anhydrous DMF (0.292 mL) was stirred at 140° C. for 16hours. After cooling, the reaction mixture was diluted with acetonitrileand methanol (4:1). The suspension was filtered and the filtrate waspurified with prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₃H₂₆F₃N₁₀O₂S (M+H)⁺: m/z=563.2; Found 563.2. ¹H NMR(500 MHz, DMSO-d₆) δ 8.60 (d, J=9.6 Hz, 1H), 8.59 (m, 1H), 8.37 (m, 1H),8.08 (s, 1H), 8.06-8.01 (m, 3H), 7.82 (s, 1H), 7.81 (s, 1H), 7.04 (t,J=7.7 Hz, 1H), 3.89-3.81 (m, 1H), 3.71 (s, 3H), 3.58 (m, 2H), 2.71 (m,2H), 2.15 (d, J=3.7 Hz, 3H), 1.96 (m, 2H), 1.57 (m, 2H). Corrected dueto presence of rotamers: ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers)δ 8.64 (s, 0.4H), 8.62 (s, 0.6H), 8.60 (s, 0.6H), 8.56 (s, 0.4H), 8.33(s, 0.6H), 8.23 (s, 0.4H), 8.15-7.95 (m, 4H), 7.83 (s, 1H), 7.82 (s,1H), 7.07-7.02 (m, 1H), 3.96-3.79 (m, 1H), 3.74-3.69 (m, 3H), 3.62-3.54(m, 2H), 2.75-2.61 (m, 2H), 2.19-2.14 (m, 3H), 2.00-1.88 (m, 2H),1.64-1.52 (m, 2H).

Example 36.4-(1-(2-Amino-3-chloropyridin-4-yl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of 3,4-dichloropyridin-2-amine (57.1 mg, 0.351 mmol),N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 72, 80 mg, 0.175 mmol), and cesium carbonate (228 mg,0.701 mmol) in anhydrous DMF (0.584 mL) was stirred at 120° C. for 2hours. After cooling, the reaction mixture was diluted with acetonitrileand methanol (4:1). The suspension was filtered and the filtrate waspurified with prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₂H₂₃ClF₃N₁₀O₂S (M+H)⁺: m/z=583.1; Found 583.1. ¹H NMR(500 MHz, DMSO-d₆) δ 8.77-8.62 (m, 1H), 8.66-8.59 (m, 1H), 8.33-8.16 (m,1H), 8.11-8.01 (m, 2H), 7.87-7.80 (m, 2H), 6.90 (d, J=5.4 Hz, 1H),3.96-3.79 (m, 1H), 3.73 (s, 3H), 3.59 (d, J=11.9 Hz, 2H), 2.74-2.62 (m,2H), 2.08-1.83 (m, 2H), 1.64-1.51 (m, 2H). Corrected due to presence ofrotamers: ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.74 (s,0.6H), 8.65 (s, 0.4H), 8.62 (s, 0.4H), 8.59 (s, 0.6H), 8.27 (s, 0.6H),8.19 (s, 0.4H), 8.11-8.01 (m, 2H), 7.87-7.80 (m, 2H), 6.90 (d, J=5.4 Hz,1H), 3.96-3.79 (m, 1H), 3.73 (s, 3H), 3.59 (d, J=11.9 Hz, 2H), 2.74-2.62(m, 2H), 2.08-1.83 (m, 2H), 1.64-1.51 (m, 2H).

Example 37.4-(1-(2-Amino-5-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of 4-chloro-5-(trifluoromethyl)pyridin-2-amine (50.3 mg, 0.256mmol),A-(1-(methylsulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 9, 50 mg, 0.128 mmol) and cesium carbonate (167 mg, 0.512mmol) in anhydrous DMF (0.427 mL) was heated at 120° C. for 2 hours.After cooling, the reaction mixture was diluted with acetonitrile andmethanol (4:1). The suspension was filtered and the filtrate waspurified with prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₀H₂₁F₆N₈O₂S (M+H)⁺: m/z=551.1; Found 551.1. ¹H NMR (500MHz, DMSO-d₆) δ 8.68-8.57 (m, 1H), 8.52-8.36 (m, 2H), 8.34-8.13 (m, 1H),8.12-8.06 (m, 1H), 6.64 (d, J=10.4 Hz, 1H), 4.12-3.94 (m, 1H), 3.55 (d,J=11.9 Hz, 2H), 2.92 (t, J=11.8 Hz, 2H), 2.87 (s, 3H), 2.06-1.89 (m,2H), 1.69-1.51 (m, 2H). Corrected due to presence of rotamers: ¹H NMR(500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.66 (s, 0.4H), 8.60 (s,0.6H), 8.51 (s, 0.6H), 8.41 (s, 1.4H), 8.32 (s, 0.6H), 8.17 (s, 0.4H),8.12-8.06 (m, 1H), 6.66 (s, 0.6H), 6.64 (s, 0.4H), 4.12-3.94 (m, 1H),3.55 (d, J=11.9 Hz, 2H), 2.98-2.82 (m, 5H), 2.06-1.89 (m, 2H), 1.69-1.51(m, 2H).

Example 38.2-((1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile

Step 1:2-(Piperidin-4-ylamino)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile

In a microwave vial with a stir bar, a mixture of tert-butyl4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 13, 2.2 g, 6.51 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole(2.70 g, 9.77 mmol), Pd(dppf)Cl₂ CH₂Cl₂ adduct (0.531 g, 0.651 mmol),and sodium carbonate (4.14 g, 39.1 mmol) in acetonitrile (13.6 mL) andwater (2.72 mL) was sparged with nitrogen and irradiated in a microwavereactor at 110° C. for 2 hours. After cooling to r.t., a 4 molarsolution of HCl in dioxane (20 mL, 80 mmol) was added and the reactionmixture was stirred at r.t. for 2 hours. The mixture was then dilutedwith MeOH (10 mL) and stirred at r.t. for an additional 30 minutes. Thereaction mixture was then diluted with water and extracted with CH₂Cl₂.The organic layer was discarded, and the aqueous layer was made basicvia the addition of a 50% aqueous solution of NaOH and extracted withCH₂Cl₂ and EtOAc. The combined organic phases were then dried over MgSO₄and concentrated. The crude material obtained was then used directlywithout further purification. LCMS calculated for C₁₅H₁₇F₃N₇ (M+H)⁺:m/z=352.1; Found 352.2.

Step 2:2-((1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile

To a mixture of2-(piperidin-4-ylamino)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile(307 mg, 0.87 mmol) in THF (5 mL) was added1-methyl-1H-imidazole-4-sulfonyl chloride (0.235 g, 1.303 mmol) followedby drop wise addition of triethylamine (0.25 mL, 1.794 mmol) and thereaction mixture was stirred at r.t. for 1 hour. The reaction mixturewas then concentrated in vacuo, and to the crude residue was addedacetonitrile, water, and several drops of TFA, and the mixture waspurified with prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₁₉H₂₁F₃N₉O₂S (M+H)⁺: m/z=496.1; Found 496.1. ¹H NMR (500MHz, DMSO-d₆) δ 8.74-8.59 (m, 2H), 8.36-8.20 (m, 2H), 7.86-7.79 (dd,J=11.7, 5.4 Hz, 2H), 5.33 (p, J=9.2 Hz, 2H), 3.96-3.77 (m, 1H), 3.72 (s,3H), 3.64-3.55 (m, 2H), 2.77-2.59 (m, 2H), 2.01-1.84 (m, 2H), 1.65-1.52(m, 2H). Corrected due to presence of rotamers: ¹H NMR (500 MHz,DMSO-d₆) (mixture of rotamers) δ 8.70 (s, 0.4H), 8.69 (s, 0.6H), 8.64(s, 0.6H), 8.61 (s, 0.4H), 8.33 (s, 0.6H), 8.28-8.20 (m, 1.4H),7.86-7.79 (m, 2H), 5.39-5.27 (m, 2H), 3.96-3.77 (m, 1H), 3.72 (s, 3H),3.64-3.55 (m, 2H), 2.77-2.59 (m, 2H), 2.01-1.84 (m, 2H), 1.65-1.52 (m,2H).

Example 39.2-((1-(Pyridin-2-ylsulfonyl)piperidin-4-yl)amino)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile

This compound was prepared according to the procedures described inExample 38, using pyridine-2-sulfonyl chloride instead of1-methyl-1H-imidazole-4-sulfonyl chloride as starting material. Purifiedwith prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₀H₂₀F₃N₈O₂S (M+H)⁺: m/z=493.1; Found: 493.1. ¹H NMR(600 MHz, DMSO-d₆) δ 8.81-8.76 (m, 1H), 8.72-8.59 (m, 2H), 8.28 (d,J=70.3 Hz, 1H), 8.27 (dd, j=7.8, 2.4 Hz, 1H), 8.16-8.09 (m, 1H), 7.94(t, j=8.4 Hz, 1H), 7.72 (dt, J=8.1, 4.3 Hz, 1H), 5.38-5.27 (m, 2H),4.03-3.85 (m, 1H), 3.81-3.65 (d, J=12.2 Hz, 2H), 2.96-2.80 (m, 1H),2.01-1.84 (m, 3H), 1.61-1.49 (m, 2H). Corrected due to presence ofrotamers: ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.81-8.76(m, 1H), 8.70 (s, 0.4H), 8.68 (s, 0.6H), 8.64 (s, 0.6H), 8.61 (s, 0.4H),8.34 (s, 0.6H), 8.29-8.24 (m, 1H), 8.22 (s, 0.4H), 8.16-8.09 (m, 1H),7.97-7.91 (m, 1H), 7.75-7.70 (m, 1H), 5.38-5.27 (m, 2H), 4.03-3.85 (m,1H), 3.78-3.69 (m, 2H), 2.96-2.80 (m, 2H), 2.01-1.84 (m, 2H), 1.61-1.49(m, 2H).

Example 40.5-Chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-amine

Step 1:5-Chloro-N-(piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-amine

A mixture of tert-butyl4-((4,5-dichloropyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 14, 100 mg, 0.288 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole(80 mg, 0.288 mmol), Pd(dppf)Cl₂ CH₂Cl₂ adduct (23.52 mg, 0.029 mmol),and sodium carbonate (122 mg, 1.152 mmol) in acetonitrile (1.2 mL) andwater (0.24 mL) was sparged with nitrogen and stirred at 80° C. for 2hours. After cooling to r.t., a 4 molar solution of HCl in 1,4-dioxane(1 mL, 4 mmol) was added and the reaction mixture was stirred at r.t.for 2 hours. The mixture was then diluted with MeOH (1 mL) and stirredat r.t. for an additional 30 minutes. The mixture was then diluted withwater and extracted with CH₂Cl₂. The organic layer was discarded and theaqueous layer was made basic via the addition of a 50% aqueous solutionof NaOH and extracted with CH₂Cl₂ and EtOAc. The combined organic phaseswere then dried over MgSO₄ and concentrated. The crude material obtainedwas then used directly without further purification. LCMS calculated forC₁₄H₁₇ClF₃N₆ (M+H)⁺: m/z=361.1; Found: 361.2.

Step 2:5-Chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-amine

To a mixture of5-chloro-N-(piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-amine(from Step 1) in THF (1.5 mL) was added 1-methyl-1H-imidazole-4-sulfonylchloride (78 mg, 0.43 mmol) followed by drop wise addition oftriethylamine (0.08 mL, 0.574 mmol) and the reaction mixture was stirredat r.t. for 1 hour. The reaction mixture was then diluted withacetonitrile, water, and several drops of TFA, and the mixture waspurified with prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₁₈H₂₁ClF₃N₈O₂S (M+H)⁺: m/z=505.1; Found 505.1.

Example 41.4-(1-(2-Methyl-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 29, using 4-fluoro-3-methylbenzaldehyde instead of3-chloro-4-fluorobenzaldehyde as starting material. Purified withprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₃H₂₉F₃N₇O₂S (M+H)⁺: m/z=524.2; Found: 524.1.

Example 42.4-(1-((1r,4r)-4-Methoxycyclohexyl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1: tert-Butyl4-((4-(1-(4-methoxycyclohexyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 1, 600 mg, 1.58 mmol),1-(4-methoxycyclohexyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 19, 482 mg, 1.58 mmol), Pd(dppf)Cl₂ CH₂Cl₂ adduct (129 mg,0.158 mmol), and sodium carbonate (1.00 g, 9.45 mmol) in acetonitrile(13.6 mL) and water (2.72 mL) was sparged with nitrogen and stirred at80° C. overnight. After cooling to r.t., the mixture was then dilutedwith water and extracted with CH₂Cl₂ and EtOAc. The combined organiclayers were then washed with brine, dried over MgSO₄, concentrated, andpurified via flash column chromatography (Agela Flash Column Silica-CS,eluting with a gradient of EtOAc/hexanes). LCMS calculated forC₂₅H₃₆F₃N₆O₃(M+H)⁺: m/z=525.3; Found: 525.2.

Step 2:4-(1-(4-Methoxycyclohexyl)-1H-pyrazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of tert-butyl4-((4-(1-(4-methoxycyclohexyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(from step 1) in THF (7.9 mL) was added a 4 molar solution of HCl in1,4-dioxane (7.9 mL, 31.6 mmol) and the reaction mixture was stirred atr.t. for 2 hours. The reaction mixture was then diluted with water andextracted with CH₂Cl₂. The organic layer was discarded, and the aqueouslayer was made basic via the addition of a 50% aqueous solution of NaOHand extracted with CH₂Cl₂ and EtOAc. The combined organic phases werethen dried over MgSO₄ and concentrated. The crude material obtained wasthen used directly without further purification. LCMS calculated forC₂₀H₂₈F₃N₆O (M+H)⁺: m/z=425.2; Found: 425.2.

Step 3:4-(1-((1r,4r)-4-Methoxycyclohexyl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of 4-(1-(4-methoxycyclohexyl)-1H-pyrazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(from Step 2, 590 mg, 0.834 mmol) and 1-methyl-1H-imidazole-4-sulfonylchloride (226 mg, 1.25 mmol) in CH₂Cl₂ (25 mL) was added triethylamine(349 μL, 2.50 mmol) and the reaction mixture was stirred at r.t. for 30minutes. The reaction mixture was then concentrated, and the residue waspurified with prep-LCMS collecting the peak with a retention time=5.7minutes out of a total run time of 7.5 minutes (Sunfire C18 column,eluting with a gradient of 35 to 50% acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₄H₃₂F₃N₈O₃S(M+H)⁺: m/z=569.2; Found: 569.2. ¹H NMR (500 MHz, DMSO-d₆) (mixture ofrotamers) δ 8.54 (s, 0.4H), 8.50 (s, 0.6H), 8.22 (s, 0.6H), 8.17 (s,0.4H), 7.96 (s, 0.6H), 7.92-7.86 (m, 1.4H), 7.84 (s, 1H), 7.81 (s, 1H),4.35-4.24 (m, 1H), 3.92-3.83 (m, 0.6H), 3.83-3.75 (m, 0.4H), 3.73 (s,3H), 3.62-3.54 (m, 2H), 3.26 (s, 3H), 3.25-3.17 (m, 1H), 2.76-2.59 (m,2H), 2.14-1.99 (m, 4H), 1.99-1.87 (m, 2H), 1.87-1.73 (m, 2H), 1.63-1.51(m, 2H), 1.37-1.25 (m, 2H).

Example 43.N-((3R,4S)-3-Fluoro-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-((trans)-4-methoxycyclohexyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 40, using tert-butyl(3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate(Intermediate 15) instead of tert-butyl4-((4,5-dichloropyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 14) and1-(4-methoxycyclohexyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 19) instead of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazoleas starting materials. Purified with prep-LCMS collecting the peak witha retention time=9.5 minutes out of a total run time of 14.5 minutes(Sunfire C18 column, eluting with a gradient of 31 to 49%acetonitrile/water containing 0.1% TEA, at flow rate of 60 mL/min). LCMScalculated for C₂₄H₃₁F₄N₈O₃S (M+H)⁺: m/z=587.2; Found: 587.2.

Example 44.4-(1-((1s,3s)-3-Amino-3-methylcyclobutyl)-1H-pyrazol-4-yl)-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:N-(Piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a solution of tert-butyl4-((4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 20, 60 mg, 0.146 mmol) in CH₂Cl₂ (0.5 mL) was added TFA(0.2 mL). After 30 minutes, the reaction mixture was concentrated toafford the desired product as the corresponding TFA salt. The crudematerial obtained was then used directly without further purification.LCMS calculated for C₁₃H₁₆F₃N₆(M+H)⁺: m/z=313.1; found 313.2.

Step 2:N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a 1 dram vial with a stir bar,N-(piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine2,2,2-trifluoroacetate (from Step 1, 50 mg, 0.12 mmol) was dissolved inCH₃CN (1 mL), then triethylamine (134 μL, 0.961 mmol) andcyclopropanesulfonyl chloride (22.5 mg, 0.160 mmol) were added. After 30minutes, saturated aqueous NaHCO₃ (3 mL) was added and the reactionmixture was extracted with CH₂Cl₂ (3×3 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated. The crude materialobtained was then used directly without further purification. LCMScalculated for C₁₆H₂₀F₃N₆O₂S (M+H)⁺: m/z=417.1; found 417.2.

Step 3:4-(1-((1s,3s)-3-amino-3-methylcyclobutyl)-1H-pyrazol-4-yl)-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture ofN-(1-(cyclopropylsulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(from step 2) in acetonitrile (1.0 mL) was added Cs₂CO₃ (104 mg, 0.320mmol) and (1r,3r)-3-((tert-butoxycarbonyl)amino)-3-methylcyclobutylmethanesulfonate (Intermediate 22, 67.1 mg, 0.240 mmol) and the reactionmixture was stirred at 100° C. for 12 hours. After cooling to r.t.,trifluoroacetic acid (TFA) (0.5 mL) was added and the reaction mixturewas stirred for 3 hours. The reaction mixture was then diluted withmethanol and purified with prep-LCMS (Sunfire C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₁H₂₉F₃N₇O₂S (M+H)⁺: m/z=500.2; Found:500.2. ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.60 (s, 0.5H),8.55 (s, 0.5H), 8.31 (s, 0.5H), 8.29 (s, 0.5H), 8.25 (s, 3H), 8.06 (s,0.5H), 8.03-7.92 (m, 1.5H), 5.09-4.98 (m, 1H), 4.00 (s, 1H), 3.66-3.57(m, 2H), 3.08-2.92 (m, 2H), 2.84-2.73 (m, 2H), 2.62-2.53 (m, 3H),2.03-1.90 (m, 2H), 1.66-1.54 (m, 2H), 1.50 (s, 3H), 1.04-0.97 (m, 2H),0.97-0.91 (m, 2H).

TABLE 2 The compounds in Table 2 were prepared in accordance with thesynthetic protocols set forth in Example 44 using the appropriatestarting materials. Ex. Name Structure Analytical data 454-(1-((1s,3s)-3-Amino-3- methylcyclobutyl)-1H- pyrazol-4-yl)-N-(1-(isopropylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 502.2 46 4-(1-((1s,3s)-3-Amino-3- methylcyclobutyl)-1H-pyrazol-4-yl)-N-(1- (cyclobutylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 514.2 47 4-(1-((1s,3r)-3-Amino-3- methylcyclobutyl)-1H-pyrazol-4-yl)-N-((3R,4S)- 1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 514.2 48 4-(1-((1s,3r)-3-Amino-3- methylcyclobutyl)-1H-pyrazol-4-yl)-N-((3R,4S)- 1-(cyclobutylsulfonyl)-3-fluoropiperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 532.2 49 4-(1-((1s,3s)-3- (Methylamino)cyclobutyl)-1H-pyrazol-4-yl)-N-(1- (pyridin-2- ylsulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 537.2 50 4-(1-((1r,3r)-3- (Methylamino)cyclobutyl)-1H-pyrazol-4-yl)-N-(1- (pyridin-2- ylsulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 537.2

Example 51.1-(4-(2-((1-(Cyclopropylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

Step 1: tert-Butyl4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 1, 400 mg, 1.050 mmol),2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol(335 mg, 1.261 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (86 mg, 0.105 mmol), and sodium carbonate (445 mg,4.20 mmol) in 1,4-dioxane (6.0 mL) and water (1.5 mL) was purged withnitrogen and stirred at 100° C. for 2 h. After cooling to r.t., thereaction mixture was diluted with water and extracted with CH₂Cl₂. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel flash column chromatography (eluting with a gradient of 0 to 10%MeOH/CH₂C₁₋₂). LCMS calculated for C₂₂H₃₂F₃N₆O₃ (M+H)⁺: m/z=485.2;Found: 485.3.

Step 2:2-Methyl-1-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol

To a mixture of tert-butyl4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(from Step 1, 1.0 g, 2.06 mmol) in CH₂Cl₂ (10.0 mL) and MeOH (0.5 mL)was added a 4 molar solution of HCl in 1,4-dioxane (1.55 mL, 6.19 mmol)and the reaction mixture was stirred at r.t. for 2 hours to form asuspension. The solid was filtered, washed with CH₂Cl₂, and dried toafford the desired product as the hydrochloride salt. LCMS calculatedfor C₁₇H₂₄F₃N₆O (M+H)⁺: m/z=385.2; Found: 385.2.

Step 3:1-(4-(2-((1-(Cyclopropylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

To a mixture of2-methyl-1-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-olhydrochloride (from Step 2, 10 mg, 0.024 mmol) in CH₂Cl₂ (0.2 mL) at 0°C. was added N,N-diisopropylethylamine (12.5 μL, 0.071 mmol) followed bydropwise addition of cyclopropanesulfonyl chloride (5.0 mg, 0.036 mmol).The reaction mixture was allowed to warm to r.t. and stirred for 1 hour.The reaction was quenched with saturated aqueous NaHCO₃ solution andextracted with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified with prep-LCMS (Sunfire C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LCMS calculated for C₂₀H₂₈F₃N₆O₃S (M+H)⁺: m/z=489.2; Found: 489.2. ¹HNMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.58 (s, 0.5H), 8.53 (s,0.5H), 8.21 (s, 0.5H), 8.18 (s, 0.5H), 8.03 (s, 0.5H), 7.95 (d, J=7.7Hz, 1H), 7.89 (s, 0.5H), 4.11 (s, 1H), 4.09 (s, 1H), 4.06-3.91 (m, 1H),3.65-3.56 (m, 2H), 3.08-2.92 (m, 2H), 2.61-2.55 (m, 1H), 2.02-1.92 (m,2H), 1.63-1.53 (m, 2H), 1.08 (s, 3H), 1.07 (s, 3H), 1.04-0.90 (m, 4H).

TABLE 3 The compounds in Table 3 were prepared in accordance with thesynthetic protocols set forth in Example 51 using the appropriatestarting materials. Ex. Name Structure Analytical data 522-Methyl-1-(4-(2-((1- (methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 463.2 53 1-(4-(2-((1- (Ethylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

LCMS found: 477.2 54 2-((1- (Cyclopropylsulfonyl)piperidin-4-yl)amino)-4-(1- (2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)pyrimidine- 5-carbonitrile

LCMS found: 446.2 ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.70(s, 0.5H), 8.62 (s, 0.5H), 8.52 (s, 0.5H), 8.46 (s, 0.5H), 8.24 (s,0.5H), 8.21 (d, J = 7.8 Hz, 1H), 8.14 (s, 0.5H), 4.13 (s, 1H), 4.12 (s,1H), 4.11-4.02 (m, 0.5H), 4.02-3.94 (m, 0.5H), 3.67-3.56 (m, 2H),3.08-2.92 (m, 2H), 2.62-2.54 (m, 1H), 2.05-1.87 (m, 2H), 1.65-1.53 (m,2H), 1.09 (s, 3H), 1.08 (s, 3H), 1.03-0.90 (m, 4H). 554-(1-(2-Hydroxy-2- methylpropyl)-1H- pyrazol-4-yl)-2-((1- (pyridin-2-ylsulfonyl)piperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found: 483.2 56 1-(4-(5-Chloro-2-((1- (cyclopropylsulfonyl)piperidin-4- yl)amino)pyrimidin-4- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

LCMS found: 455.2 57 1-(4-(2-(((3R,4S)-1- (Cyclopropylsulfonyl)-3-fluoropiperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found: 507.2 58 1-(4-(2-(((3R,4S)-3- Fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found: 481.2 ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.59(s, 0.5H), 8.57 (s, 0.5H), 8.21 (s, 1H), 8.12-8.02 (m, 1.5H), 7.93 (s,0.5H), 5.10-4.82 (m, 1H), 4.32-4.06 (m, 3H), 3.90-3.77 (m, 1H),3.71-3.58 (m, 1H), 3.34-3.09 (m, 1H), 3.09-2.96 (m, 1H), 2.93 (s, 1.5H),2.92 (s, 1.5H), 2.03-1.88 (m, 1H), 1.84- 1.72 (m, 1H), 1.08 (s, 6H). 591-(4-(2-(((3R,4S)-1- (Cyclopropylsulfonyl)-3- methylpiperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

LCMS found: 503.2 60 2-Methyl-1-(4-(2- (((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazol-4- yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 543.2 61 2-Methyl-1-(4-(2- (((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 543.2 62 2-Methyl-1-(4-(2- (((3R,4S)-3-methyl-1- (pyridin-2-ylsulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 540.2

Example 63.2-Methyl-1-(4-(2-((1-((3-morpholinopropyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol

Step 1:1-(4-(2-((1-((3-Chloropropyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

To a mixture of2-methyl-1-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-olhydrochloride (Example 51, Step 2, 200 mg, 0.475 mmol) in CH₂Cl₂ (2.4mL) at 0° C. was added N,N-diisopropylethylamine (249 μL, 1.426 mmol)followed by dropwise addition of 3-chloropropane-1-sulfonyl chloride(126 mg, 0.713 mmol). The reaction mixture was allowed to warm to r.t.and stirred for 1 hour. The reaction was quenched with saturated aqueousNaHCO₃ solution and extracted with CH₂Cl₂. The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude product was used directly in the next step withoutfurther purification. LCMS calculated for C₂₀H₂₉ClF₃N₆O₃S (M+H)⁺:m/z=525.2; Found: 525.2.

Step 2:2-Methyl-1-(4-(2-((1-((3-morpholinopropyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol

A mixture of1-(4-(2-((1-((3-chloropropyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol(10 mg, 0.019 mmol), morpholine (5.0 mg, 0.057 mmol), potassiumcarbonate (7.9 mg, 0.057 mmol), and potassium iodide (1.3 mg, 7.7 μmol)in acetonitrile (0.2 mL) was stirred at 100° C. for 3 h. After beingcooled to r.t., the reaction mixture was diluted with methanol andpurified with prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₄H₃₇F₃N₇O₄S (M+H)⁺: m/z=576.3; Found: 576.3. ¹H NMR(500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.58 (s, 0.5H), 8.53 (s,0.5H), 8.20 (s, 0.5H), 8.18 (s, 0.5H), 8.02 (s, 0.5H), 7.96 (d, J=7.8Hz, 1H), 7.90 (s, 0.5H), 4.11 (s, 1H), 4.09 (s, 1H), 4.05-3.93 (m, 3H),3.69-3.58 (m, 4H), 3.51-3.41 (m, 2H), 3.28-2.94 (m, 8H), 2.16-2.04 (m,2H), 2.04-1.88 (m, 2H), 1.65-1.49 (m, 2H), 1.08 (s, 3H), 1.07 (s, 3H).

TABLE 4 The compounds in Table 4 were prepared in accordance with thesynthetic protocols set forth in Example 63 using the appropriatestarting materials. Ex. Name Structure Analytical data 641-(4-(2-((1-((3- (Diethylamino)propyl) sulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin- 4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

LCMS found: 562.3 65 1-(4-(2-((1-((3- (Azetidin-1- yl)propyl)sulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found: 546.2 66 2-Methyl-1-(4-(2-((1- ((3-(pyrrolidin-1-yl)propyl)sulfonyl) piperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 560.3 ¹H NMR (500 MHz, DMSO- d₆) (mixture of rotamers) δ8.58 (s, 0.5H), 8.53 (s, 0.5H), 8.20 (s, 0.5H), 8.18 (s, 0.5H), 8.02 (s,0.5H), 7.96 (d, J = 7.7 Hz, 1H), 7.89 (s, 0.5H), 4.10 (s, 1H), 4.10 (s,1H), 4.09-3.94 (m, 1H), 3.66-3.51 (m, 4H), 3.31-3.21 (m, 2H), 3.21- 3.13(m, 2H), 3.09-2.94 (m, 4H), 2.12-1.93 (m, 6H), 1.92-1.80 (m, 2H), 1.63-1.51 (m, 2H), 1.07 (s, 6H). 67 2-Methyl-1-(4-(2-((1- ((3-(piperidin-1-yl)propyl)sulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 574.3 68 2-Methyl-1-(4-(2-((1- ((3-(4-methylpiperazin-1-yl)propyl)sulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 589.3 69 4-(3-((4-((4-(1-(2- Hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidin- 2-yl)amino)piperidin-1-yl)sulfonyl)propyl) piperazin-2-one

LCMS found: 589.3 70 4-(3-((4-((4-(1-(2- Hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidin- 2-yl)amino)piperidin-1-yl)sulfonyl)propyl)-1- methylpiperazin-2-one

LCMS found: 603.3 71 (S)-2-Methyl-1-(4-(2- ((1-((3-(3- methylmorpholino)propyl)sulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 590.3 72 (R)-2-Methyl-1-(4-(2- ((1-((3-(3- methylmorpholino)propyl)sulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 590.3 73 1-(4-(2-((1-((3-(7-Oxa-4- azaspiro[2.5]octan-4-yl)propyl)sulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found: 602.3 74 (S)-1-(4-(2-((1-((3-(3- (Methoxymethyl)pyrrolidin-1-yl) propyl)sulfonyl) piperidin-4-yl)amino)-5-(trifluoromethyl) pyrimidin- 4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found: 604.3 75 1-(3-((4-((4-(1-(2- Hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidin- 2-yl)amino)piperidin-1-yl)sulfonyl)propyl) piperidin-4-ol

LCMS found: 590.3 76 1-(3-((4-((4-(1-(2- Hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl) pyrimidin- 2-yl)amino)piperidin-1-yl)sulfonyl)propyl) piperidine-4-carbonitrile

LCMS found: 599.3 77 1-(4-(2-((1-((3-(4- Methoxypiperidin-1-yl)propyl)sulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found: 604.3 78 1-(4-(2-((1-((4- (Dimethylamino)butyl)sulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found: 548.3 79 1-(4-(2-((1-((4- (Diethylamino)butyl)sulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found: 576.3 80 2-Methyl-1-(4-(2-((1-((4- (pyrrolidin-1-yl)butyl)sulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 574.3 81 2-Methyl-1-(4-(2-((1-((4- (piperidin-1-yl)butyl)sulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 588.3

Example 82.2-Methyl-1-(4-(2-((1-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol

To a mixture of2-methyl-1-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-olhydrochloride (Example 51, Step 2, 20 mg, 0.048 mmol) in acetonitrile(0.24 mL) at 0° C. was added N,N-diisopropylethylamine (24.9 μL, 0.143mmol) followed by drop wise addition of 2-chloroethane-1-sulfonylchloride (11.62 mg, 0.071 mmol). After being stirred at r.t. for 1 hour,pyrrolidine (10.1 mg, 0.143 mmol) was added and the reaction mixture wasstirred at 60° C. for 2 hours. The reaction was quenched with saturatedaqueous NaHCO₃ solution and extracted with CH₂Cl₂. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified with prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₃H₃₅F₃N₇O₃S (M+H)⁺:m/z=546.2; Found: 546.2.

TABLE 5 The compounds in Table 5 were prepared in accordance with thesynthetic protocols set forth in Example 82 using the appropriatestarting materials. Ex. Name Structure Analytical data 831-(4-(2-((1-((2- (Dimethylamino)ethyl) sulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

LCMS found: 520.2 84 2-Methyl-1-(4-(2-((1-((2- morpholinoethyl)sulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)propan-2-ol

LCMS found: 562.2

Example 85.2-Methyl-1-(4-(2-((1-((1-methylazetidin-3-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol

Step 1: tert-Butyl3-((4-((4-(I-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)azetidine-1-carboxylate

To a mixture of2-methyl-1-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-olhydrochloride (Example 51, Step 2, 100 mg, 0.238 mmol) in CH₂Cl₂ (1.2mL) at 0° C. was added N,N-diisopropylethylamine (124 μL, 0.713 mmol)followed by dropwise addition of tert-butyl3-(chlorosulfonyl)azetidine-1-carboxylate (72.9 mg, 0.285 mmol). Thereaction mixture was allowed to warm to r.t. and stirred for 1 hour. Thereaction was quenched with saturated aqueous NaHCO₃ solution andextracted with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was used directly in the next step without further purification.LCMS calculated for C₂₅H₃₇F₃N₇O₅S (M+H)⁺: m/z=604.3; Found: 604.4.

Step 2:2-Methyl-1-(4-(2-((1-((1-methylazetidin-3-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol

A mixture of tert-butyl3-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)azetidine-1-carboxylate(10 mg, 0.017 mmol) in CH₂Cl₂ (0.1 mL) and TFA (0.05 mL) was stirred atr.t. for 1 hour. The reaction mixture was concentrated under reducedpressure. To the residue was added tetrahydrofuran (0.2 mL) and a 37 wt% solution of formaldehyde in H₂O (3.7 μL, 0.050 mmol) followed bysodium triacetoxyborohydride (10.5 mg, 0.050 mmol). After being stirredat r.t. for 2 hours, the reaction mixture was diluted with methanol andpurified with prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₁H₃₁F₃N₇O₃S (M+H)⁺: m/z=518.2; Found: 518.2.

TABLE 6 The compounds in Table 6 were prepared in accordance with thesynthetic protocols set forth in Example 85 using the appropriatestarting materials. Ex. Name Structure Analytical data 86(±)-2-Methyl-1-(4-(2-((1- ((1-methylpyrrolidin-3-yl)sulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 532.2 87 2-Methyl-1-(4-(2-((1-((1- methylpiperidin-4-yl)sulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1- yl)propan-2-ol

LCMS found: 546.2

Example 88.1-(4-(2-((1-((4-(Dimethylamino)cyclohexyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

To a mixture of2-methyl-1-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-olhydrochloride (Example 50, Step 2, 20 mg, 0.048 mmol) in CH₂Cl₂ (0.4 mL)at 0° C. was added N,N-diisopropylethylamine (24.9 μL, 0.143 mmol)followed by dropwise addition of 4-oxocyclohexane-1-sulfonyl chloride(11.2 mg, 0.057 mmol). After being stirred at r.t. for 1 hour, a 2.0 Msolution of dimethylamine in THF (71.3 μL, 0.143 mmol) was added to thereaction mixture followed by sodium triacetoxyborohydride (30.2 mg,0.143 mmol). After being stirred at r.t. for 2 hours, the reactionmixture was diluted with methanol and purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% NH₄OH, at flow rate of 60 mL/min).

Peak 1: retention time on analytical LC-MS (pH=10,acetonitrile/water+NH₄OH) t_(r)=1.14 min, LCMS calculated forC₂₅H₃₉F₃N₇O₃S (M+H)⁺: m/z=574.3; Found: 574.3;

Peak 2: retention time on analytical LC-MS (pH=10,acetonitrile/water+NH₄OH) t_(r)=1.21 min, LCMS calculated forC₂₅H₃₉F₃N₇O₃S (M+H)⁺: m/z=574.3; Found: 574.3.

TABLE 7 The compounds in Table 7 were prepared in accordance with thesynthetic protocols set forth in Example 88 using the appropriatestarting materials. Ex. Name Structure Analytical data 891-(4-(2-((1-((4- (Diethylamino)cyclohexyl) sulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

Peak 1: Retention time on analytical LCMS (pH = 10) t_(r) = 1.46 minLCMS found: 602.3 Peak 2: Retention time on analytical LCMS (pH = 10)t_(r) = 1.52 min LCMS found: 602.3 90 1-(4-(2-((1-((4-(Azetidin-1-yl)cyclohexyl)sulfonyl) piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

Peak 1: Retention time on analytical LCMS (pH = 10) t_(r) = 1.28 minLCMS found: 586.3 Peak 2: Retention time on analytical LCMS (pH = 10)t_(r) = 1.42 min LCMS found: 586.3 91 2-Methyl-1-(4-(2-((1-((4-(pyrrolidin-1- yl)cyclohexyl)sulfonyl) piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1- yl)propan-2-ol

Peak 1: Retention time on analytical LCMS (pH = 10) t_(r) = 1.36 minLCMS found: 600.4 Peak 2: Retention time on analytical LCMS (pH = 10)t_(r) = 1.55 min LCMS found: 600.4

Example 92.3-((4-((4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)propan-1-ol

To a mixture of2-methyl-1-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-olhydrochloride (Example 51, Step 2, 10 mg, 0.024 mmol) in THF (0.24 mL)at 0° C. was added N,N-diisopropylethylamine (12.5 μL, 0.071 mmol)followed by dropwise addition of methyl 3-(chlorosulfonyl)propanoate(5.3 mg, 0.029 mmol). After being stirred at r.t. for 1 hour, LiAlH₄(1.0 M solution in THF, 71.3 μL, 0.071 mmol) was added. After beingstirred at r.t. for 1 hour, the reaction was quenched by carefuladdition of a 20% aqueous solution of NaOH. The suspension was filteredand the filtrate was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₀H₃₀F₃N₆O₄S (M+H)⁺:m/z=507.2; Found: 507.2.

TABLE 8 The compound in Table 8 was prepared in accordance with thesynthetic protocols set forth in Example 92 using the appropriatestarting materials. Ex. Name Structure Analytical data 934-((4-((4-(1-(2-Hydroxy- 2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)amino)piperidin-1-yl)sulfonyl)butan-1-ol

LCMS found: 521.2

Example 94.4-((4-((4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-methylbutan-2-ol

A mixture of2-methyl-1-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-olhydrochloride (Example 51, Step 2, 10 mg, 0.024 mmol) in THF (0.24 mL)was cooled to 0° C. before N,N-diisopropylethylamine (12.5 μL, 0.071mmol) was added followed by drop wise addition of methyl 3-(chlorosulfonyl)propanoate (5.3 mg, 0.029 mmol). The reaction mixture was thenwarmed to r.t. and stirred for 1 hour. A 3 molar solution ofmethylmagnesium bromide in Et₂O (23.8 μL, 0.071 mmol) was then added andthe reaction mixture was stirred at r.t. for 1 hour. The reaction wasthen quenched by careful addition of TFA (0.1 mL). The resulting mixturewas then diluted with MeOH and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₂H₃₄F₃N₆O₄S(M+H)⁺: m/z=535.2; Found: 535.2.

Example 95.(±)-1,1,1-Trifluoro-2-methyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol

A mixture ofN-(1-(methylsulfonyl)piperidin-4-yl)-4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 9, 10 mg, 0.026 mmol), 2-methyl-2-(trifluoromethyl)oxirane(16.15 mg, 0.128 mmol), and cesium carbonate (25.0 mg, 0.077 mmol) inacetonitrile (0.15 mL) was stirred at 90° C. for 3 hours. After coolingto r.t., the reaction mixture was diluted with methanol and purifiedwith prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₁₈H₂₃F₆N₆O₃S (M+H)⁺: m/z=517.1; Found: 517.2.

Example 96.2-Methyl-2-(4-(2-((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanamide

Step 1: tert-Butyl4-(4-(1-(1-amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of tert-butyl4-((4-(1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 20, 400 mg, 0.970 mmol), 2-bromo-2-methylpropanamide (322mg, 1.940 mmol), and cesium carbonate (948 mg, 2.91 mmol) inacetonitrile (5.0 mL) was stirred at 90° C. for 2 hours. After beingcooled to r.t., the reaction mixture was diluted with water andextracted with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel flash column chromatography (eluting with agradient of 0 to 10% MeOH/CH₂C₁₋₂). LCMS calculated for C₂₂H₃₁F₃N₇O₃(M+H)⁺: m/z=498.2; Found: 498.3.

Step 2:2-Methyl-2-(4-(2-((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanamide

To a mixture of tert-butyl4-((4-(1-(1-amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(10 mg, 0.020 mmol) in THF (0.2 mL) was added a 4 molar solution of HClin 1,4-dioxane (15.1 μL, 0.060 mmol) and the reaction mixture wasstirred at 80° C. for 2 hours. After being cooled to 0° C.,N,N-diisopropylethylamine (17.6 μL, 0.100 mmol) was added to thereaction mixture followed by dropwise addition of pyridine-2-sulfonylchloride (4.3 mg, 0.024 mmol). The reaction mixture was allowed to warmto r.t. and stirred for 1 hour. The reaction was quenched with saturatedaqueous NaHCO₃ solution and extracted with CH₂Cl₂. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified with prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₂H₂₆F₃N₈O₃S (M+H)⁺:m/z=539.2; Found: 539.2. ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers)δ 8.78 (d, J=4.1 Hz, 1H), 8.55 (s, 0.5H), 8.52 (s, 0.5H), 8.23 (s,0.5H), 8.17 (s, 0.5H), 8.16-8.09 (m, 1H), 8.00 (s, 0.5H), 7.97-7.91 (m,2H), 7.90 (s, 0.5H), 7.76-7.69 (m, 1H), 7.27 (s, 1H), 7.11 (s, 1H), 3.94(s, 0.5H), 3.88 (s, 0.5H), 3.78-3.66 (m, 2H), 2.98-2.79 (m, 2H),2.02-1.84 (m, 2H), 1.73 (s, 6H), 1.62-1.47 (m, 2H).

TABLE 9 The compounds in Table 9 were prepared in accordance with thesynthetic protocols set forth in Example 96 using the appropriatestarting materials. Ex. Name Structure Analytical data 97 2-(4-(2-((1-(Ethylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropanamide

LCMS found: 490.2 98 2-(4-(2-((1- (Cyclopropylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropanamide

LCMS found: 502.2 ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.60(s, 0.5H), 8.54 (s, 0.5H), 8.25 (s, 0.5H), 8.20 (s, 0.5H), 8.04 (s,0.5H), 7.97 (d, J = 7.7 Hz, 1H), 7.92 (s, 0.5H), 7.28 (s, 1H), 7.13 (s,1H), 4.00 (broad, 1H), 3.67- 3.52 (m, 2H), 3.17-2.80 (m, 2H), 2.62-2.54(m, 1H), 2.06- 1.88 (m, 2H), 1.75 (s, 3H), 1.74 (s, 3H), 1.65-1.53 (m,2H), 1.06-0.88 (m, 4H).

Example 99.4-(1-(2-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

Step 1:4-(1-(2-Chloro-4-formylphenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

A mixture of4-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Intermediate 26, 1.263 g, 4.00 mmol),3-chloro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzaldehyde(Intermediate 23, 1.995 g, 6.00 mmol), Pd(dppf)Cl₂ CH₂Cl₂ adduct (0.327g, 0.400 mmol), and sodium carbonate (1.060 g, 10.00 mmol) in CH₃CN(16.67 mL) and water (3.33 mL) was purged with nitrogen and stirred at80° C. for 2 hours. After cooling to r.t., the reaction mixture wasdiluted with water and extracted with EtOAc and CH₂Cl₂. The combinedorganic phases were then washed with brine, dried over MgSO₄, andconcentrated. The crude material obtained was then used directly withoutfurther purification. LCMS calculated for C₂₁H₂₁ClN₇O₃S (M+H)⁺:m/z=486.1; Found: 486.1.

Step 2:4-(1-(2-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

To a mixture of4-(1-(2-chloro-4-formylphenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(from step 1) in THF (20 mL) was added 1-methylpiperazine (1.20 g, 12.0mmol) followed by drop wise addition of TFA (2.0 mL) and the reactionmixture was stirred at ambient temperature for 10 minutes. Sodiumtriacetoxyborohydride (1.695 g, 8.00 mmol) was then added portion-wiseand the reaction mixture was stirred at ambient temperature for 2 hours.The reaction mixture was then diluted with acetonitrile and water andpurified by prep-LCMS (XBridge C₁₋₈ column, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).Fractions containing the desired product were concentrated and purifiedwith prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₆H₃₃ClN₉O₂S (M+H)⁺: m/z=570.2; Found: 570.3. ¹H NMR(500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.85 (s, 0.6H), 8.78 (s,0.8H), 8.70 (s, 0.6H), 8.52 (s, 0.6H), 8.39 (s, 0.4H), 8.36-8.29 (m,1H), 7.74-7.66 (m, 2H), 7.54-7.47 (m, 1H), 4.15-4.05 (m, 0.6H),4.05-3.94 (m, 0.4H), 3.70 (s, 2H), 3.60-3.51 (m, 2H), 3.46-3.33 (m, 2H),3.15-3.02 (m, 2H), 3.02-2.83 (m, 7H), 2.80 (s, 3H), 2.46-2.30 (m, 2H),2.04-1.92 (m, 2H), 1.67-1.54 (m, 2H).

Example 100.N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:3-Methyl-4-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzaldehyde

A mixture of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 1, 610 mg, 1.60 mmol),3-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzaldehyde(Intermediate 24, 750 mg, 2.403 mmol), Pd(dppf)Cl₂ CH₂Cl₂ adduct (131mg, 0.160 mmol), and sodium carbonate (424 mg, 4.00 mmol) in CH₃CN (6.67mL) and water (1.33 mL) was purged with nitrogen and stirred at 80° C.for 2 hours. After cooling to r.t., a 4 molar solution of HCl in1,4-dioxane (8.0 mL, 32 mmol) was added and the reaction mixture wasstirred at r.t. for 2 hours. The mixture was then diluted with MeOH (4mL) and stirred at r.t. for an additional 30 minutes. The reactionmixture was then diluted with water and extracted with CH₂Cl₂. Theorganic layer was discarded, and the aqueous layer was made basic viathe addition of a 50% aqueous solution of NaOH and extracted with CH₂Cl₂and EtOAc. The combined organic phases were then dried over MgSO₄ andconcentrated. The crude material obtained was then used directly withoutfurther purification. LCMS calculated for C₂₁H₂₂F₃N₆O (M+H)⁺: m/z=431.2;Found: 431.2.

Step 2:N-(1-(#l-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of3-methyl-4-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzaldehyde(from step 1) in THF (8 mL) was added 1-methyl-1H-imidazole-4-sulfonylchloride (434 mg, 2.40 mmol) followed by dropwise addition oftriethylamine (447 μL, 3.20 mmol) and the reaction mixture was stirredat ambient temperature for 1 hour before heating to 60° C. for 30minutes. After cooling to r.t., 1-methylpiperazine (481 mg, 4.81 mmol)was added followed by dropwise addition of TFA (0.8 mL) and the reactionmixture was stirred at ambient temperature for 10 minutes. Sodiumtriacetoxyborohydride (679 mg, 3.20 mmol) was then added portion-wiseand the reaction mixture was stirred at ambient temperature for 2 hours.The reaction mixture was then diluted with acetonitrile and water andpurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).Fractions containing the desired product were concentrated and purifiedwith prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₃₀H₃₈F₃N₁₀O₂S (M+H)⁺: m/z=659.3; Found: 659.2. ¹H NMR(500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.61 (s, 0.4H), 8.57 (s,0.6H), 8.41 (s, 0.6H), 8.31 (s, 0.4H), 8.21 (s, 0.6H), 8.11 (s, 0.4H),8.01-7.96 (m, 1H), 7.85-7.79 (m, 2H), 7.47-7.39 (m, 2H), 7.38-7.32 (m,1H), 3.97-3.79 (m, 1H), 3.79-3.68 (m, 5H), 3.63-3.53 (m, 2H), 3.49-3.35(m, 2H), 3.16-2.96 (m, 4H), 2.80 (s, 3H), 2.76-2.61 (m, 2H), 2.47-2.33(m, 2H), 2.22 (s, 3H), 2.01-1.88 (m, 2H), 1.64-1.53 (m, 2H).

TABLE 10 The compounds in Table 10 were prepared in accordance with thesynthetic protocols set forth in Example 100 using the appropriatestarting materials. Ex. Name Structure Analytical data 101N-((3R,4S)-3-Fluoro-1- (methylsulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4- ((4-methylpiperazin-1- yl)methyl)phenyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 611.3 ¹H NMR (600 MHz, DMSO- d₆) (mixture of rotamers) δ 8.66(s, 0.4H), 8.64 (s, 0.6H), 8.48 (s, 0.6H), 8.36 (s, 0.4H), 8.28 (s,0.6H), 8.21-8.07 (m, 1.4H), 7.49- 7.40 (m, 2H), 7.37 (s, 0.6H), 7.36 (s,0.4H), 5.08-4.87 (m, 1H), 4.35-4.14 (m, 1H), 3.91-3.70 (m, 3H), 3.67 (d,J = 12.2 Hz, 1H), 3.60-2.95 (m, 8H), 2.92 (s, 3H), 2.80 (s, 3H), 2.60-2.40 (m, 2H), 2.24 (s, 3H), 2.04-1.93 (m, 1H), 1.84- 1.77 (m, 1H). 102N-((3R,4S)-3-Fluoro-1- ((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-4-((4- methylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 677.3 103 N-((3R,4S)-3-Fluoro-1- ((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-4-((4- methylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 677.4 104 1-(4-(4-(4-(2-(((3R,4S)-3- Fluoro-1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)-3-methylbenzyl)piperazin- 1-yl)ethan-1-one

LCMS found 705.4 ¹H NMR (500 MHz, DMSO- d₆) (mixture of rotamers) δ 8.63(s, 1H), 8.51 (s, 0.6H), 8.40 (s, 0.4H), 8.31 (s, 0.6H), 8.17 (s, 0.4H),8.13 (d, J = 7.3 Hz, 0.6H), 8.06 (d, J = 7.3 Hz, 0.4H), 7.86- 7.81 (m,2H), 7.61-7.47 (m, 3H), 5.06-4.84 (m, 1H), 4.54-4.30 (m, 4H), 4.24- 3.94(m, 3H), 3.94-3.84 (m, 1H), 3.75-3.64 (m, 4H), 3.48-3.31 (m, 2H), 3.18-2.81 (m, 3H), 2.75-2.62 (m, 1H), 2.28 (s, 3H), 2.05 (s, 3H), 2.03-1.94(m, 1H), 1.83-1.76 (m, 1H). 105 1-(4-(3-Methyl-4-(4-(2-((1-((1-methyl-1H- imidazol-4- yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1- yl)benzyl)piperazin-1-yl)ethan-1-one

LCMS found 687.1 106 4-(1-(4- ((Dimethylamino)methyl)-2-methylphenyl)-1H- pyrazol-4-yl)-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 604.1 107 N-(1-((1-Methyl-1H- imidazol-4-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-4-(morpholinomethyl)phenyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 646.1 108 5-Chloro-4-(1-(2-chloro- 4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)pyrimidin-2-amine

LCMS found 645.3 109 5-Chloro-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-4-((4- methylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)pyrimidin-2- amine

LCMS found 625.3 110 5-Chloro-N-(1-((1- methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-4-((4- methylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)pyrimidin-2- amine

LCMS found 625.3 111 4-(1-(2-Chloro-4-((4- methylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)-2-(((3R,4S)- 3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 588.2

Example 112.4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

Step 1:4-(1-(2-Chloro-4-formylphenyl)-1H-pyrazol-4-yl)-2-(piperidin-4-ylamino)pyrimidine-5-carbonitrile

A mixture of tert-butyl4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 13, 1.351 g, 4.00 mmol),3-chloro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzaldehyde(Intermediate 23, 2.00 g, 6.01 mmol), Pd(dppf)Cl₂ CH₂Cl₂ adduct (0.327g, 0.400 mmol), and sodium carbonate (1.06 g, 10.0 mmol) in CH₃CN (16.7mL) and water (3.33 mL) was purged with nitrogen and stirred at 80° C.for 2 hours. After cooling to r.t., a 4 molar solution of HCl in1,4-dioxane (20.0 mL, 80.0 mmol) was added and the reaction mixture wasstirred at r.t. for 2 hours. The mixture was then diluted with MeOH (10mL) and stirred at r.t. for an additional 30 minutes. The reactionmixture was then diluted with water and extracted with CH₂Cl₂. Theorganic layer was discarded, and the aqueous layer was made basic viathe addition of a 50% aqueous solution of NaOH and extracted with CH₂Cl₂and EtOAc. The combined organic phases were then dried over MgSO₄ andconcentrated. The crude material obtained was then used directly withoutfurther purification. LCMS calculated for C₂₀H₁₉ClN₇O (M+H)⁺: m/z=408.1;Found: 408.1.

Step 2:4-(1-(2-Chloro-4-formylphenyl)-1H-pyrazol-4-yl)-2-(piperidin-4-ylamino)pyrimidine-5-carbonitrile

To a mixture of4-(1-(2-chloro-4-formylphenyl)-1H-pyrazol-4-yl)-2-(piperidin-4-ylamino)pyrimidine-5-carbonitrile(from step 1) in THF (20 mL) was added ethanesulfonyl chloride (514 mg,4.00 mmol) followed by dropwise addition of triethylamine (0.56 mL, 4.0mmol) and the reaction mixture was stirred at r.t. for 1 hour. MeOH (20mL) was then added followed by a 33 wt % solution of methylamine (5 mL,40 mmol) in EtOH and the reaction mixture was stirred at ambienttemperature for 1 hour before heating to 70° C. for 30 minutes. Thereaction mixture was then concentrated in vacuo, and to the cruderesidue was added MeOH (20 mL) and THF (20 mL) followed by portion-wiseaddition of sodium borohydride (303 mg, 8.00 mmol), then the reactionmixture was stirred at ambient temperature for 30 minutes. The reactionmixture was then diluted with acetonitrile, water, and TFA (0.3 mL) andpurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).Fractions containing the desired product were concentrated and purifiedwith prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₃H₂₈ClN₈O₂S (M+H)⁺: m/z=515.2; Found: 515.2. ¹H NMR(500 MHz, DMSO-d₆) (mixture of rotamers) δ 8.99-8.87 (m, 2.6H), 8.84 (s,0.4H), 8.78 (s, 0.4H), 8.70 (s, 0.6H), 8.54 (s, 0.6H), 8.41 (s, 0.4H),8.37-8.30 (m, 1H), 7.91-7.86 (m, 1H), 7.85-7.79 (m, 1H), 7.68-7.62 (m,1H), 4.29-4.21 (m, 2H), 4.17-4.07 (m, 0.6H), 4.07-3.97 (m, 0.4H),3.67-3.56 (m, 2H), 3.11-2.91 (m, 4H), 2.65-2.58 (m, 3H), 2.01-1.89 (m,2H), 1.64-1.51 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

TABLE 11 The compounds in Table 11 were prepared in accordance with thesynthetic protocols set forth in Example 112 using the appropriatestarting materials. Ex. Name Structure Analytical data 1134-(1-(2-Chloro-4- ((methylamino)methyl)phenyl)- 1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 501.1 ¹H NMR (600 MHz, DMSO-d₆) (mixture of rotamers) δ8.96-8.86 (m, 2.6H), 8.84 (s, 0.4H), 8.79 (s, 0.4H), 8.71 (s, 0.6H),8.53 (s, 0.6H), 8.41 (s, 0.4H), 8.37-8.30 (m, 1H), 7.90-7.86 (m, 1H),7.85- 7.80 (m, 1H), 7.67-7.62 (m, 1H), 4.29-4.21 (m, 2H), 4.16-3.95 (m,1H), 3.61-3.52 (m, 2H), 2.98- 2.82 (m, 5H), 2.65-2.59 (m, 3H), 2.04-1.92(m, 2H), 1.67-1.55 (m, 2H). 114 4-(1-(2-Chloro-4- ((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)- 2-((1- (cyclopropylsulfonyl) piperidin-4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 527.2 ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ8.99-8.86 (m, 2.6H), 8.84 (s, 0.4H), 8.79 (s, 0.4H), 8.70 (s, 0.6H),8.55 (s, 0.6H), 8.41 (s, 0.4H), 8.37-8.30 (m, 1H), 7.91-7.86 (m, 1H),7.85- 7.80 (m, 1H), 7.68-7.62 (m, 1H), 4.31-4.20 (m, 2H), 4.17-4.07 (m,0.6H), 4.07-3.96 (m, 0.4H), 3.69- 3.56 (m, 2H), 3.09-2.93 (m, 2H),2.66-2.54 (m, 4H), 2.04-1.91 (m, 2H), 1.68-1.54 (m, 2H), 1.04- 0.90 (m,4H). 115 4-(1-(2-Chloro-4- ((ethylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 515.1 116 4-(1-(2-Chloro-4- ((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2- (((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 519.1 ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ9.03-8.89 (m, 2.6H), 8.86 (s, 0.4H), 8.81 (s, 0.4H), 8.75 (s, 0.6H),8.58 (s, 0.6H), 8.52-8.40 (m, 1.4H), 7.90-7.87 (m, 1H), 7.83 (d, J = 3.5Hz, 0.4H), 7.81 (d, J = 3.5 Hz, 0.6H), 7.67-7.63 (m, 1H), 5.08-4.84 (m,1H), 4.38- 4.15 (m, 3H), 3.90-3.79 (m, 1H), 3.73-3.62 (m, 1H), 3.36-3.13(m, 1H), 3.08-2.97 (m, 1H), 2.94- 2.90 (m, 3H), 2.65-2.59 (m, 3H),2.05-1.93 (m, 1H), 1.84-1.77 (m, 1H). 117 4-(1-(2-Chloro-4-((methylamino)methyl) phenyl)-1H-pyrazol-4-yl)-2- (((3R,4S)-1-(ethylsulfonyl)-3- fluoropiperidin-4- yl)amino)pyrimidine-5-carbonitrile

LCMS found 533.3 ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers) δ9.02-8.90 (m, 2.6H), 8.86 (s, 0.4H), 8.81 (s, 0.4H), 8.76 (s, 0.6H),8.59 (s, 0.6H), 8.50-8.39 (m, 1.4H), 7.91-7.86 (m, 1H), 7.83 (d, J = 3.1Hz, 0.4H), 7.81 (d, J = 3.1 Hz, 0.6H), 7.68-7.62 (m, 1H), 5.03-4.81 (m,1H), 4.40- 4.16 (m, 3H), 3.92-3.83 (m, 1H), 3.74-3.65 (m, 1H), 3.43-3.20(m, 1H), 3.15-3.03 (m, 3H), 2.65- 2.59 (m, 3H), 2.02-1.90 (m, 1H),1.82-1.74 (m, 1H), 1.23 (t, J = 7.3 Hz, 3H). 118 4-(1-(2-Chloro-4-((methylamino)methyl) phenyl)-1H-pyrazol-4-yl)-2- (((3R,4S)-3-fluoro-1-(propylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 547.0 119 4-(1-(2-Chloro-4- ((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2- (((3R,4S)-3-fluoro-1- (isopropylsulfonyl)piperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 547.0 120 4-(1-(2-Chloro-4- ((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2- (((3R,4S)-1- (cyclopropylsulfonyl)-3-fluoropiperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 545.0 121 4-(1-(2-Chloro-4- ((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2- (((3R,4S)-1- (cyclobutylsulfonyl)-3-fluoropiperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 559.0 122 4-(1-(2-Chloro-4- ((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2- (((3R,4S)-1-((3- cyanopropyl)sulfonyl)-3-fluoropiperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 572.0 123 N-((3R,4S)-1- (Cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)-4- (1-(2-methyl-4- ((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 568.2 124 5-Chloro-4-(1-(2-chloro-4- ((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)- N-(1- (methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine

LCMS found 510.1 125 4-(1-(6- ((Ethylamino)methyl)-2-methylpyridin-3-yl)-1H- pyrazol-4-yl)-2-((1- (ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 510.3 126 2-((1-((1-Methyl-1H- imidazol-4-yl)sulfonyl)piperidin-4- yl)amino)-4-(1-(2- methyl-6-((methylamino)methyl) pyridin-3-yl)-1H-pyrazol-4- yl)pyrimidine-5-carbonitrile

LCMS found 548.3 127 4-(1-(6- ((Ethylamino)methyl)-2-methylpyridin-3-yl)-1H- pyrazol-4-yl)-2-((1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 562.3

Example 128.4-(1-(2-Methyl-4-(((methyl-d₃)amino)methyl)phenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:3-Methyl-4-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzaldehyde

A mixture of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 1, 1.00 g, 2.63 mmol),3-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzaldehyde(Intermediate 24, 0.984 g, 3.15 mmol), Pd(dppf)Cl₂ CH₂Cl₂ adduct (0.214g, 0.263 mmol), and sodium carbonate (0.696 g, 6.57 mmol) inacetonitrile (11 mL) and water (2.2 mL) was stirred at 80° C. overnight.After cooling to r.t., a 4 molar solution of HCl in 1,4-dioxane (13 mL,52 mmol) was added and the reaction mixture was stirred at r.t. for 2hours. The mixture was then diluted with MeOH (6.5 mL) and stirred atr.t. for an additional 30 minutes. The reaction mixture was then dilutedwith water and extracted with CH₂Cl₂. The organic layer was discarded,and the aqueous layer was made basic via the addition of a 50% aqueoussolution of NaOH and extracted with CH₂Cl₂ and EtOAc. The organic phaseswere then dried over MgSO₄ and concentrated. The crude material obtainedwas then used directly without further purification. LCMS calculated forC₂₁H₂₂F₃N₆O (M+H)⁺: m/z=431.2; Found: 431.2.

Step 2:4-(1-(2-Methyl-4-(((methyl-d₃)amino)methyl)phenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of3-methyl-4-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzaldehyde(from step 1) in THF (6.5 mL) was added methanesulfonyl chloride (0.3mL, 3.9 mmol) and triethylamine (732 μL, 5.25 mmol) and the reactionmixture was stirred at r.t. for 1 hour. MeOH (6.5 mL) was then addedfollowed by methan-d₃-amine hydrochloride (0.556 g, 7.88 mmol) andtriethylamine (1.1 mL, 7.89 mmol) and the reaction mixture was stirredat ambient temperature for 1 hour before heating to 70° C. for 30minutes. The reaction mixture was then concentrated in vacuo, and to thecrude residue was added MeOH (6.5 mL) and THF (6.5 mL) followed byportion-wise addition of sodium borohydride (0.199 g, 5.25 mmol), thenthe reaction mixture was stirred at ambient temperature for 30 minutes.The reaction mixture was then diluted with acetonitrile, water, and TFA(0.2 mL) and purified with prep-LCMS (Sunfire C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₃H₂₆D₃F₃N₇O₂S (M+H)⁺: m/z=527.2; Found:527.2. ¹H NMR (600 MHz, DMSO-d₆) (mixture of rotamers) δ 8.84 (s, 2H),8.66 (s, 0.4H), 8.60 (s, 0.6H), 8.47 (s, 0.6H), 8.38 (s, 0.4H), 8.25 (s,0.6H), 8.14 (s, 0.4H), 8.06 (d, J=7.8 Hz, 0.6H), 8.04 (d, J=7.8 Hz,0.4H), 7.58-7.51 (m, 2H), 7.50-7.45 (m, 1H), 4.22-4.15 (m, 2H),4.11-4.03 (m, 0.6H), 4.03-3.94 (m, 0.4H), 3.60-3.51 (m, 2H), 2.97-2.83(m, 5H), 2.30-2.23 (m, 3H), 2.04-1.93 (m, 2H), 1.65-1.56 (m, 2H).

TABLE 12 The compounds in Table 12 were prepared in accordance with thesynthetic protocols set forth in Example 128 using the appropriatestarting materials. Ex. Name Structure Analytical data 129 N-(1-(Ethylsulfonyl)piperidin- 4-yl)-4-(1-(2-methyl-4- (((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 541.2 130 N-(1- (Cyclopropylsulfonyl)piperidin-4-yl)-4-(1-(2- methyl-4-(((methyl- d₃)amino)methyl)phenyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 553.2 131 N-(1-((1-Methyl-1H- pyrazol-3-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-4- (((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 593.3 132 N-((3R,4S)-3-Fluoro-1- (methylsulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4- (((methyl- d₃)amino)methyl)phenyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 545.3 133 N-((3R,4S)-1- (Cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)-4- (1-(2-methyl-4-(((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 571.3 134 5-Chloro-4-(1-(2-chloro- 4-(((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)pyrimidin-2-amine

LCMS found 513.2 135 5-Chloro-4-(1-(2-chloro- 4-(((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-N-(1-(cyclopropylsulfonyl)piperidin- 4-yl)pyrimidin-2- amine

LCMS found 539.2 136 5-Chloro-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-4- (((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4- yl)pyrimidin-2-amine

LCMS found 559.2 137 5-Chloro-N-(1-((1- methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-4- (((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4- yl)pyrimidin-2-amine

LCMS found 559.2 138 4-(1-(2-Chloro-4- (((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 504.2 ¹H NMR (600 MHz, DMSO- d₆) (mixture of rotamers) δ8.97-8.86 (m, 2.6H), 8.84 (s, 0.4H), 8.79 (s, 0.4H), 8.71 (s, 0.6H),8.53 (s, 0.6H), 8.41 (s, 0.4H), 8.38-8.31 (m, 1H), 7.91-7.86 (m, 1H),7.85- 7.80 (m, 1H), 7.67-7.62 (m, 1H), 4.29-4.21 (m, 2H), 4.15-3.95 (m,1H), 3.61- 3.52 (m, 2H), 2.98-2.83 (m, 5H), 2.04-1.92 (m, 2H), 1.67-1.55(m, 2H). 139 4-(1-(2-Chloro-4- (((methyl- d₃)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2((1- (ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 518.2 ¹H NMR (600 MHz, DMSO- d₆) (mixture of rotamers) δ8.99-8.88 (m, 2.6H), 8.84 (s, 0.4H), 8.78 (s, 0.4H), 8.70 (s, 0.6H),8.54 (s, 0.6H), 8.41 (s, 0.4H), 8.37-8.31 (m, 1H), 7.90-7.86 (m, 1H),7.85- 7.80 (m, 1H), 7.68-7.62 (m, 1H), 4.29-4.21 (m, 2H), 4.17-4.07 (m,0.6H), 4.07- 3.97 (m, 0.4H), 3.67-3.57 (m, 2H), 3.11-2.91 (m, 4H),2.01-1.89 (m, 2H), 1.64- 1.51 (m, 2H), 1.22 (t, J = 7.4 Hz, 3H). 1404-(1-(2-Chloro-4- (((methyl- d₃)amino)methyl- d)phenyl)-1H-pyrazol-4-yl)-2-((1- (ethylsulfonyl)piperidin- 4-yl)amino)pyrimidine-5-carbonitrile

LCMS found 519.2 141 4-(1-(2-Chloro-4- (((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2-((1- (cyclopropylsulfonyl)piperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 530.2 142 4-(1-(2-Chloro-4- (((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2-((1-((1-methyl-1H-pyrazol-3- yl)sulfonyl)piperidin-4- yl)amino)pyrimidine-5-carbonitrile

LCMS found 570.2 143 4-(1-(2-Chloro-4- (((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2- (((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 522.2 144 4-(1-(2-Chloro-4- (((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2- (((3R,4S)-1-(ethylsulfonyl)-3- fluoropiperidin-4- yl)amino)pyrimidine-5-carbonitrile

LCMS found 536.3 145 4-(1-(2-Chloro-4- (((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2- (((3R,4S)-1-(cyclopropylsulfonyl)-3- fluoropiperidin-4- yl)amino)pyrimidine-5-carbonitrile

LCMS found 548.2 ¹H NMR (500 MHz, DMSO- d₆) (mixture of rotamers) δ8.98-8.85 (m, 3H), 8.81 (s, 0.4H), 8.75 (s, 0.6H), 8.60 (s, 0.6H),8.50-8.39 (m, 1.4H), 7.91-7.86 (m, 1H), 7.85- 7.80 (m, 1H), 7.68-7.62(m, 1H), 5.07-4.83 (m, 1H), 4.40-4.18 (m, 3H), 3.94- 3.84 (m, 1H),3.73-3.65 (m, 1H), 3.44-3.21 (m, 1H), 3.17-3.05 (m, 1H), 2.63- 2.55 (m,1H), 2.09-1.95 (m, 1H), 1.85-1.76 (m, 1H), 1.05-0.91 (m, 4H). 1464-(1-(2-Chloro-4- (((methyl- d₃)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2- (((3R,4S)-1- (cyclopropylsulfonyl)-3-methylpiperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 544.2 147 4-(1-(2-Chloro-4- (((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2- (((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazol-3- yl)sulfonyl)piperidin-4- yl)amino)pyrimidine-5-carbonitrile

LCMS found 584.3 148 4-(1-(2-Chloro-4- (((methyl-d₃)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2- (((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)amino)pyrimidine-5-carbonitrile

LCMS found 584.3 149 2-((1-((1-Methyl-1H- pyrazol-4-yl)sulfonyl)piperidin-4- yl)amino)-4-(1-(2- methyl-6-(((methyl-d₃)amino)methyl)pyridin- 3-yl)-1H-pyrazol-4- yl)pyrimidine-5-carbonitrile

LCMS found 551.3 150 2-(((3R,4S)-3-Methyl-1- ((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)amino)-4-(1-(2- methyl-6-(((methyl-d₃)amino)methyl)pyridin- 3-yl)-1H-pyrazol-4- yl)pyrimidine-5-carbonitrile

LCMS found 565.3

Example 151.4-(1-(6-((Isopropylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

Step 1:4-(I-(6-Formyl-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-(piperidin-4-ylamino)pyrimidine-5-carbonitrile

A mixture of tert-butyl4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 13, 101 mg, 0.299 mmol),6-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)picolinaldehyde(Intermediate 25, 112 mg, 0.359 mmol), Pd(dppf)Cl₂ CH₂Cl₂ adduct (24.4mg, 0.030 mmol), and sodium carbonate (79 mg, 0.747 mmol) in CH₃CN (1.25mL) and water (0.25 mL) was purged with nitrogen and stirred at 80° C.overnight. After cooling to r.t., a 4 molar solution of HCl in1,4-dioxane (1.5 mL, 6.0 mmol) was added and the reaction mixture wasstirred at r.t. for 2 hours. The mixture was then diluted with MeOH (1mL) and stirred at r.t. for an additional 30 minutes. The reactionmixture was then diluted with water and extracted with CH₂Cl₂. Theorganic layer was discarded, and the aqueous layer was made basic viathe addition of a 50% aqueous solution of NaOH and extracted with CH₂Cl₂and EtOAc. The combined organic phases were then dried over MgSO₄ andconcentrated. The crude material obtained was then used directly withoutfurther purification. LCMS calculated for C₂₀H₂₁N₈O (M+H)⁺: m/z=389.2;Found: 389.1.

Step 2:4-(1-(6-((Isopropylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

To a mixture of4-(1-(6-formyl-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-(piperidin-4-ylamino)pyrimidine-5-carbonitrile(from step 1) in THF (1.5 mL) was added 1-methyl-1H-imidazole-4-sulfonylchloride (81 mg, 0.45 mmol) followed by dropwise addition oftriethylamine (83 μL, 0.60 mmol) and the reaction mixture was stirred atr.t. for 1 hour. MeOH (1.5 mL) was then added followed by propan-2-amine(53 mg, 0.90 mmol) and the reaction mixture was stirred at ambienttemperature for 1 hour before heating to 70° C. for 30 minutes. Thereaction mixture was then concentrated in vacuo, and to the cruderesidue was added MeOH (1.5 mL) and THF (1.5 mL) followed byportion-wise addition of sodium borohydride (22.6 mg, 0.597 mmol), thenthe reaction mixture was stirred at ambient temperature for 30 minutes.The reaction mixture was then diluted with acetonitrile, water, andseveral drops of TFA and purified with prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₇H₃₄N₁₁O₂S (M+H)⁺:m/z=576.3; Found: 576.3.

TABLE 13 The compounds in Table 13 were prepared in accordance with thesynthetic protocols set forth in Example 151 using the appropriatestarting materials. Ex. Name Structure Analytical data 1524-(1-(6-((tert- Butylamino)methyl)-2- methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-((1- methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 590.3 153 2-((1- (Cyclopropylsulfonyl)piperidin-4-yl)amino)-4-(1- (6- ((isopropylamino)methyl)-2-methylpyridin-3-yl)- 1H-pyrazol-4- yl)pyrimidine-5- carbonitrile

LCMS found 536.3 154 4-(1-(2-Chloro-4- ((((1s,3s)-3-cyanocyclobutyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-(((3R,4S)-1-(cyclopropylsulfonyl)- 3-fluoropiperidin-4- yl)amino)pyrimidine-5-carbonitrile

LCMS found 610.0 155 4-(1-(2-chloro-4- ((((1r,3r)-3-hydroxy-1-methylcyclobutyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-(((3R,4S)-1-(cyclopropylsulfonyl)- 3-fluoropiperidin-4- yl)amino)pyrimidine-5-carbonitrile

LCMS found 615.0 156 4-(1-(2-Chloro-4-((((1- hydroxycyclopropyl)methyl)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2- (((3R,4S)-1-(cyclopropylsulfonyl)-3- fluoropiperidin-4- yl)amino)pyrimidine-5-carbonitrile

LCMS found 601.0

Example 157.4-(1-(2-Chloro-4-(((1-hydroxy-2-methylpropan-2-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

To a mixture of4-(1-(2-chloro-4-formylphenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Example 99, Step 7, 20 mg, 0.041 mmol) in CH₂Cl₂ (0.5 mL) was added2-amino-2-methylpropan-1-ol (11 mg, 0.12 mmol) andN-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol) and the reactionmixture was stirred at r.t. for 30 minutes before sodiumtriacetoxyborohydride (26.2 mg, 0.123 mmol) was added and the reactionmixture was stirred at r.t. overnight. The reaction mixture was thenconcentrated, and to the crude residue was added methanol/water (5:1,v/v) and the mixture was purified with prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₅H₃₂ClN₈O₃S (M+H)⁺:m/z=559.2; Found: 559.3.

TABLE 14 The compounds in Table 14 were prepared in accordance with thesynthetic protocols set forth in Example 157 using the appropriatestarting materials. Ex. Name Structure Analytical data 1584-(1-(2-Chloro-4- ((((1s,3s)-3-hydroxy-1- methylcyclobutyl)amino)methyl)phenyl)-1H- pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 571.2 159 4-(1-(2-Chloro-4-(((1- (hydroxymethyl)cyclopropyl)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 557.3 160 2-((3-Chloro-4-(4-(5- cyano-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidin-4- yl)-1H-pyrazol-1-yl)benzyl)amino)-2- methylpropanamide

LCMS found 572.2 161 4-(1-(2-Chloro-4- ((((1r,3r)-3-hydroxycyclobutyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 557.2 162 4-(1-(2-Chloro-4- ((((1s,3s)-3-hydroxycyclobutyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 557.2 163 4-(1-(2-Chloro-4- ((((1s,3s)-3-methoxycyclobutyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 571.2 164 4-(1-(2-Chloro-4- ((((1s,3s)-3-cyanocyclobutyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 566.2

Example 165.4-(1-(2-Chloro-4-(((1-methyl-1H-pyrazol-4-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

To a mixture of4-(1-(2-chloro-4-formylphenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Intermediate 27, 15 mg, 0.030 mmol) and 1-methyl-1H-pyrazol-4-amine(5.8 mg, 0.060 mmol) in CH₂Cl₂ (1 mL) was added TFA (0.5 mL) and thereaction mixture was stirred at r.t. for 30 minutes beforetriethylsilane (0.5 mL, 3.13 mmol) was added and the reaction mixturewas stirred at r.t. for 3 hours. The reaction mixture was thenconcentrated, and to the crude residue was added methanol and themixture was purified with prep-LCMS (Sunfire C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₆H₃₀ClN₁₀O₂S (M+H)⁺: m/z=581.2; Found:581.3.

Example 166. Methyl(2-((3-chloro-4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)amino)cyclohexyl)carbamate

Step 1: Methyl (2-aminocyclohexyl)carbamate

To a mixture of tert-butyl (2-aminocyclohexyl)carbamate (50 mg, 0.23mmol) in CH₂Cl₂ (2 mL) was added methyl chloroformate (20 μL, 0.26 mmol)followed by dropwise addition of triethylamine (81 μL, 0.58 mmol) andthe reaction mixture was stirred at r.t. for 1 hour. The reactionmixture was then concentrated in vacuo, and to the residue was added a2:1 mixture of CH₂Cl₂/TFA (2 mL) and the reaction mixture was stirred atr.t. for 1 hour. The reaction mixture was then concentrated in vacuo toafford methyl (2-aminocyclohexyl)carbamate as the corresponding TFAsalt. The crude material obtained was used directly without furtherpurification. LCMS calculated for C₈H₁₇N₂O₂ (M+H)⁺: m/z=173.1; Found:173.2.

Step 2: Methyl(2-((3-chloro-4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)amino)cyclohexyl)carbamate

To a mixture of4-(1-(2-chloro-4-formylphenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Example 99, Step 7, 13 mg, 0.027 mmol) and methyl(2-aminocyclohexyl)carbamate 2,2,2-trifluoroacetate (Step 1, 11.5 mg,0.040 mmol) in MeOH (1 mL) was added triethylamine (81 μL, 0.58 mmol)and the reaction mixture was stirred at 70° C. for 1 hour. Sodiumcyanoborohydride (14.7 mg, 0.233 mmol) was then added, and the reactionmixture was stirred at 70° C. for 2 hours. After cooling to r.t., thereaction mixture was then diluted with methanol and purified withprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₉H₃₇ClN₉O₄S (M+H)⁺: m/z=642.2; Found: 642.2.

TABLE 15 The compounds in Table 15 were prepared in accordance with thesynthetic protocols set forth in Example 166 using the appropriatestarting materials. Ex. Name Structure Analytical data 167 Methyl(S)-3-((3-chloro- 4-(4-(5-cyano-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4- yl)-1H-pyrazol-1- yl)benzyl)amino)piperidine-1-carboxylate

LCMS found 628.4 168 Methyl (R)-3-((3-chloro- 4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidin-4- yl)-1H-pyrazol-1-yl)benzyl)amino)piperidine- 1-carboxylate

LCMS found 628.4 169 (S)-4-(1-(4-(((1- Acetylpyrrolidin-3-yl)amino)methyl)-2- chlorophenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 598.3 170 (R)-4-(1-(4-(((1- Acetylpyrrolidin-3-yl)amino)methyl)-2- chlorophenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 598.3 171 4-(1-(4-(((1- Acetylazetidin-3- yl)amino)methyl)-2-chlorophenyl)-1H- pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 584.3 172 Methyl 3-((3-chloro-4-(4- (5-cyano-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidin-4- yl)-1H-pyrazol-1-yl)benzyl)amino)azetidine- 1-carboxylate

LCMS found 600.3

Example 173.4-(1-(2-Chloro-4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

To a mixture of4-(1-(2-chloro-4-formylphenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Example 99, Step 7, 10 mg, 0.021 mmol) in methanol (1 mL) was added(1s,4s)-4-amino-1-methylcyclohexan-1-ol (4 mg, 0.03 mmol) and thereaction mixture was stirred at 70° C. for 1 hour. Sodiumcyanoborohydride (3.9 mg, 0.062 mmol) was then added, and the reactionmixture was stirred at 70° C. for 2 hours. After cooling to r.t., thereaction mixture was then diluted with methanol and purified withprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₈H₃₆ClN₈O₃S (M+H)⁺: m/z=599.2; Found: 599.3.

TABLE 16 The compounds in Table 16 were prepared in accordance with thesynthetic protocols set forth in Example 173 using the appropriatestarting materials. Ex. Name Structure Analytical data 1744-(1-(2-Chloro-4- ((((1r,4r)-4-hydroxy-4- methylcyclohexyl)amino)methyl)phenyl)-1H- pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 599.3 175 4-(1-(2-Chloro-4- ((((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin- 4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 613.3 176 4-(1-(2-Chloro-4- ((((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin- 4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 613.3 177 4-(1-(2-Chloro-4- ((((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl) amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 653.3 178 4-(1-(2-Chloro-4- ((((1R,2R)-2-hydroxycyclohexyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 585.1 179 4-(1-(2-Chloro-4- ((((1R,2S)-2-hydroxycyclohexyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 585.2 180 4-(1-(2-Chloro-4- ((((1S,3R)-3-hydroxycyclohexyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 585.3 181 4-(1-(2-Chloro-4- ((((1S,3S)-3-hydroxycyclohexyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 585.3 182 4-(1-(2-Chloro-4- ((((1r,4r)-4-hydroxycyclohexyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 585.2 183 4-(1-(2-Chloro-4-(((4- cyanocyclohexyl)amino)methyl)phenyl)-1H- pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 594.2 184 4-(1-(2-Chloro-4-(((2- (dimethylamino)cyclohexyl)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 612.3 185 4-(1-(2-Chloro-4-((((cis)- 4-(methylsulfonyl)cyclohexyl) amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 647.3 186 4-(1-(2-Chloro-4- ((((1R,2R)-2-hydroxycyclopentyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 571.3 187 4-(1-(2-Chloro-4- ((((1S,2S)-2-hydroxycyclopentyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 571.3 188 4-(1-(2-Chloro-4- ((((1S,3R)-3-hydroxycyclopentyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 571.3 189 4-(1-(2-Chloro-4- ((((1R,3R)-3-hydroxycyclopentyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 571.3 190 4-(1-(2-Chloro-4- ((((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 571.3 191 4-(1-(2-Chloro-4- ((((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 571.3 192 4-(1-(2-Chloro-4- ((((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin- 4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 585.2 193 4-(1-(2-Chloro-4- ((((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin- 4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 585.2 194 4-(1-(2-Chloro-4-((((1- ethyl-1H-pyrazol-4-yl)methyl)amino)methyl) phenyl)-1H-pyrazol-4- yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 595.3 195 (R)-4-(1-(2-Chloro-4- (((tetrahydro-2H-pyran-3-yl)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 571.3 196 (S)-4-(1-(2-Chloro-4- (((tetrahydro-2H-pyran-3-yl)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 571.3 197 Ethyl 4-((3-chloro-4-(4- (5-cyano-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidin-4- yl)-1H-pyrazol-1-yl)benzyl)amino)piperidine- 1-carboxylate

LCMS found 642.2 198 (±)-4-(1-(2-Chloro-4- (((1- (methylsulfonyl)pyrrolidin-3- yl)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 634.2 199 4-(1-(2-Chloro-4-(((2- (trifluoromethoxy)ethyl)amino)methyl)phenyl)-1H- pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 599.1 200 4-(1-(2-Chloro-4-(((2- (methylsulfonyl)ethyl)amino)methyl)phenyl)-1H- pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 593.1

Example 201.1-(4-(2-(((3R,4S)-3-Fluoro-1-((3-morpholinopropyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

Step 1: tert-Butyl(3R,4S)-3-fluoro-4-((4-(I-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of tert-butyl(3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate(Intermediate 15, 200 mg, 0.502 mmol),2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol(160 mg, 0.602 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (41 mg, 0.050 mmol), and sodium carbonate (213 mg,2.006 mmol) in 1,4-dioxane (2.4 mL) and water (0.6 mL) was purged withnitrogen and stirred at 100° C. for 2 hours. After cooling to r.t., thereaction mixture was diluted with water and extracted with CH₂Cl₂. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel flash column chromatography (eluting with a gradient of 0 to 10%MeOH/CH₂C₁₋₂). LCMS calculated for C₂₂H₃₁F₄N₆O₃ (M+H)⁺: m/z=503.2;Found: 503.2.

Step 2:1-(4-(2-(((3R,4S)-3-Fluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

To a mixture of tert-butyl(3R,4S)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(from Step 1, 100 mg, 0.199 mmol) in CH₂Cl₂ (1.0 mL) and MeOH (0.05 mL)was added a 4 molar solution of HCl in 1,4-dioxane (1.55 mL, 6.19 mmol).After being stirred at r.t. for 2 hours, the reaction mixture wasconcentrated to afford the desired product as the hydrochloride salt.LCMS calculated for C₁₇H₂₃F₄N₆O (M+H)⁺: m/z=403.2; Found: 403.2.

Step 3:1-(4-(2-(((3R,4S)-1-((3-Chloropropyl)sulfonyl)-3-fluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

To a mixture of1-(4-(2-(((3R,4S)-3-fluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-olhydrochloride (from Step 2, 100 mg, 0.228 mmol) in CH₂Cl₂ (1.2 mL) at 0°C. was added N,N-diisopropylethylamine (119 μL, 0.684 mmol), followed bydrop wise addition of 3-chloropropane-1-sulfonyl chloride (48.4 mg,0.273 mmol). The reaction mixture was allowed to warm to r.t. andstirred for 1 hour. The reaction was quenched with saturated aqueousNaHCO₃ solution and extracted with CH₂Cl₂. The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure to give the desired product. LCMS calculated forC₂₀H₂₈ClF₄N₆O₃S (M+H)⁺: m/z=543.2; Found: 543.2.

Step 4:1-(4-(2-(((3R,4S)-3-Fluoro-1-((3-morpholinopropyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

A mixture of1-(4-(2-(((3R,4S)-1-((3-chloropropyl)sulfonyl)-3-fluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol(from Step 3, 10 mg, 0.018 mmol), morpholine (4.8 mg, 0.055 mmol),potassium carbonate (7.6 mg, 0.055 mmol), and potassium iodide (1.3 mg,7.37 μmol) in acetonitrile (0.2 mL) was stirred at 100° C. for 3 hours.After being cooled to r.t., the reaction mixture was diluted withmethanol and purified with prep-LCMS (Sunfire C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₄H₃₆F₄N₇O₄S (M+H)⁺: m/z=594.2; Found:594.2.

TABLE 17 The compounds in Table 17 were prepared in accordance with thesynthetic protocols set forth in Example 201 using the appropriatestarting materials. Ex. Name Structure Analytical data 2021-(4-(2-(((3R,4S)-1-((3- (Diethylamino)propyl)sulfonyl)-3-fluoropiperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 580.3 203 1-(4-(2-(((3R,4S)-3- Fluoro-1-((3-(pyrrolidin- 1-yl)propyl)sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 578.3 204 1-(4-(2-(((3R,4S)-3- Fluoro-1-((3-(piperidin-1-yl)propyl)sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 592.3 205 1-(4-(2-(((3R,4S)-1-((3- (Dimethylamino)propyl)sulfonyl)-3- fluoropiperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 552.2 206 1-(4-(2-(((3R,4S)-3- Fluoro-1-((3-((R)-3-methoxypyrrolidin-1- yl)propyl)sulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 608.3 207 1-(4-(2-(((3R,4S)-3- Fluoro-1-((3-(4-methoxypiperidin-1- yl)propyl)sulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 622.3 208 1-(3-(((3R,4S)-3-Fluoro- 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)propyl) piperidin-4-ol

LCMS found 608.3 209 1-(4-(2-(((3R,4S)-3- Fluoro-1-((3-(4-methylpiperazin-1- yl)propyl)sulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 607.3 210 1-(4-(2-(((3R,45)-1-((3- (4-Ethylpiperazin-1-yl)propyl)sulfonyl)-3- fluoropiperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 621.3 211 1-(4-(2-(((3R,4S)-3- Fluoro-1-((3-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan- 2- yl)propyl)sulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

LCMS found 619.3 212 4-(3-(((3R,4S)-3-Fluoro- 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)propyl)-1- methylpiperazin-2-one

LCMS found 621.3 213 2-((1-((3- (Diethylamino)propyl)sulfonyl)piperidin-4- yl)amino)-4-(1-(2- hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)pyrimidine- 5-carbonitrile

LCMS found 519.3 214 4-(1-(2-Hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-2-((1-((3- (pyrrolidin-1- yl)propyl)sulfonyl) piperidin-4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 517.3 215 4-(1-(2-Hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-2-((1-((3- (piperidin-1- yl)propyl)sulfonyl) piperidin-4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 531.3 216 2-((1-((4- (Diethylamino)butyl)sulfonyl)piperidin-4- yl)amino)-4-(1-(2- hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)pyrimidine- 5-carbonitrile

LCMS found 533.3 217 4-(1-(2-Hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-2-((1-((4- (pyrrolidin-1- yl)butyl)sulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 531.3 218 4-(1-(2-Hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-2-((1-((4- (piperidin-1- yl)butyl)sulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 545.3 219 (S)-1-(4-(2-((1-((3-(3- Methoxypyrrolidin-1-yl)propyl)sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 590.3 220 (R)-1-(4-(2-((1-((3-(3- Methoxypyrrolidin-1-yl)propyl)sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 590.3 221 (S)-1-(4-(2-((1-((3-(2- (Methoxymethyl)azetidin- 1-yl)propyl)sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 590.3 222 1-(4-(2-((1-((3-((1S,4S)- 2-Oxa-5-azabicyclo[2.2.1]heptan- 5- yl)propyl)sulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 588.3 223 (R)-1-(3-((4-((4-(1-(2- Hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)propyl)-3- methylpyrrolidin-3-ol

LCMS found 590.3 224 (R)-1-(3-((4-((4-(1-(2- Hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)propyl) pyrrolidin-3-ol

LCMS found 576.3 225 1-(3-((4-((4-(1-(2- Hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin- 2-yl)amino)piperidin-1-yl)sulfonyl)propyl)azetidin- 3-ol

LCMS found 562.3 226 1-(4-(2-((1-((3- (Cyclopropylamino)propyl)sulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- 2-methylpropan-2-ol

LCMS found 546.2

Example 227.1-(4-(2-((1-((2-Hydroxyethyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

To a mixture of2-methyl-1-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-olhydrochloride (Example 51, Step 2, 20 mg, 0.048 mmol) in CH₂Cl₂ (0.24mL) at 0° C. was added N,N-diisopropylethylamine (24.9 μL, 0.143 mmol)followed by drop wise addition of 2-methoxyethane-1-sulfonyl chloride(7.54 mg, 0.048 mmol). The reaction mixture was allowed to warm to r.t.and stirred for 1 hour. The reaction mixture was then cooled to −78° C.and treated with a 1.0 M solution of boron tribromide in CH₂Cl₂ (95 μL,0.095 mmol). After being stirred at −78° C. for 1 hour, the reaction wasquenched with saturated aqueous NaHCO₃ solution and extracted withCH₂Cl₂. The combined organic layers were dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified withprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₁₉H₂₈F₃N₆O₄S (M+H)⁺: m/z=493.2; Found: 493.2.

Example 228.N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-(piperazin-1-ylmethyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:3-Methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzaldehyde

To a mixture of3-methyl-4-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzaldehyde(Example 100, Step 7, 406 mg, 0.942 mmol) in THF (4.71 mL) was added1-methyl-1H-imidazole-4-sulfonyl chloride (255 mg, 1.41 mmol), followedby dropwise addition of triethylamine (263 μL, 1.89 mmol), and thereaction mixture was stirred at ambient temperature for 1 hour beforeheating to 60° C. for 30 minutes. After cooling to r.t., the reactionmixture was then diluted with water and extracted with CH₂Cl₂ and EtOAc.The combined organic layers were then dried over MgSO₄ and concentrated.The crude material obtained was used directly without furtherpurification. LCMS calculated for C₂₅H₂₆F₃N₈O₃S (M+H)⁺: m/z=575.2;Found: 575.0.

Step 2:N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-(piperazin-1-ylmethyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of3-methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzaldehyde(from Step 1, 23 mg, 0.040 mmol) in THF (0.2 mL) was added tort-butylpiperazine-1-carboxylate (22.4 mg, 0.120 mmol), followed by dropwiseaddition of TFA (20 μL), and the reaction mixture was stirred at r.t.for 10 minutes before sodium triacetoxyborohydride (17 mg, 0.080 mmol)was added and the reaction mixture was stirred at r.t. for 2 hours. A 4molar solution of HCl in dioxane (200 μL, 0.80 mmol) was then added andthe reaction mixture was stirred at r.t. for 1 hour before heating to60° C. for 30 minutes. After cooling to r.t., the reaction mixture wasthen diluted with methanol and water and purified with prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₉H₃₆F₃N₁₀O₂S (M+H)⁺: m/z=645.3; Found: 645.2.

Example 229.(R)-(1-Methyl-4-(3-methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)piperazin-2-yl)methanol

To a mixture of3-methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzaldehyde(Example 228, Step 7, 23 mg, 0.040 mmol) in THF (0.2 mL) was addedtert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate (26.0 mg, 0.120mmol) followed by dropwise addition of TFA (20 μL) and the reactionmixture was stirred at r.t. for 10 minutes before sodiumtriacetoxyborohydride (17 mg, 0.080 mmol) was added and the reactionmixture was stirred at r.t. for 2 hours. A 4 molar solution of HCl indioxane (200 μL. 0.80 mmol) was then added and the reaction mixture wasstirred at r.t. for 1 hour before heating to 60° C. for 30 minutes.After cooling to r.t., the reaction mixture was concentrated in vacuo,and to the crude residue was added THF (0.2 mL), a 37% aqueous solutionof formaldehyde (30 μL, 0.40 mmol), and AcOH (0.1 mL) and the reactionmixture was stirred at r.t. for 10 minutes. Sodium triacetoxyborohydride(16.97 mg, 0.080 mmol) was then added and the reaction mixture wasstirred at ambient temperature overnight. The reaction mixture was thendiluted with methanol and water and purified with prep-LCMS (Sunfire C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₃₁H₄₀F₃N₁₀O₃S(M+H)⁺: m/z=689.3; Found: 689.5.

Example 230.(S)-2-(1-Methyl-4-(3-methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)piperazin-2-yl)acetonitrile

This compound was prepared according to the procedures described inExample 229 using tert-butyl (S)-2-(cyanomethyl)piperazine-1-carboxylateinstead of tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate asstarting material. LCMS calculated for C₃₂H₃₉F₃N₁₁O₂S (M+H)⁺: m/z=698.3;Found: 698.4.

TABLE 18 The compounds in Table 18 were prepared in accordance with thesynthetic protocols set forth in Example 100 using the appropriatestarting materials. Ex. Name Structure Analytical data 2314-(1-(2-Methyl-4-((4- methylpiperazin-1- yl)methyl)phenyl)-1H-pyrazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 593.3 232 4-(1-(4-((4- Ethylpiperazin-1- yl)methyl)-2-methylphenyl)-1H- pyrazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine

LCMS found 607.3 233 N-(1- (Ethylsulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4- ((4-methylpiperazin-1- yl)methyl)phenyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 607.4 234 N-(1- (Cyclopropylsulfonyl)piperidin-4-yl)-4-(1-(2- methyl-4-((4- methylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 619.4 235 4-(1-(4-((4- Ethylpiperazin-1- yl)methyl)-2-methylphenyl)-1H- pyrazol-4-yl)-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 673.4 236 4-(1-(4-((4- (Cyclopropylmethyl)piperazin-1-yl)methyl)-2- methylphenyl)-1H- pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 699.4 237 1-Methyl-4-(3-methyl-4- (4-(2-((1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-pyrazol-1-yl)benzyl)piperazin-2-one

LCMS found 673.3 238 4-(1-(2-Chloro-4-((4- ethylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 584.3 239 4-(1-(2-chloro-4-((4- methylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)-2-((1- (ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 584.3 240 4-(1-(2-Chloro-4-((4- methyl-3-oxopiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 584.2 241 4-(1-(2-Chloro-4-((4- ethylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 650.3 242 2-((1- (Cyclopropylsulfonyl)piperidin-4-yl)amino)-4-(1- (2-methyl-4-((4- methylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)pyrimidine- 5-carbonitrile

LCMS found 576.3 243 2-((1-((1-Methyl-1H- imidazol-4-yl)sulfonyl)piperidin-4- yl)amino)-4-(1-(2- methyl-4-((4-methylpiperazin-1- yl)methyl)phenyl)-1H- pyrazol-4-yl)pyrimidine-5-carbonitrile

LCMS found 616.4 244 2-(4-(5-Chloro-2-((1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)amino)pyrimidin-4- yl)-1H-pyrazol-1-yl)-5-((4-methylpiperazin-1- yl)methyl)benzonitrile

LCMS found 636.4 245 5-Chloro-4-(1-(4-((4- ethylpiperazin-1-yl)methyl)-2- methylphenyl)-1H- pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)pyrimidin-2-amine

LCMS found 639.3 246 5-Chloro-4-(1-(4-((4- (cyclopropylmethyl)piperazin-1-yl)methyl)-2- methylphenyl)-1H- pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)pyrimidin-2-amine

LCMS found 665.3 247 5-Chloro-4-(1-(4-((4- isopropylpiperazin-1-yl)methyl)-2- methylphenyl)-1H- pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazole-4- yl)sulfonyl)piperidin-4- yl)pyrimidin-2-amine

LCMS found 653.2 248 4-(4-(4-(5-Chloro-2-((1- ((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)amino)pyrimidin-4- yl)-1H-pyrazol-1-yl)-3-methylbenzyl)-1- methylpiperazin-2-one

LCMS found 639.3 249 5-Chloro-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-6-((4- methylpiperazin-1-yl)methyl)pyridin-3-yl)- 1H-pyrazol-4- yl)pyrimidin-2-amine

LCMS found 626.2 250 5-Chloro-4-(1-(6-((4- ethylpiperazin-1-yl)methyl)-2- methylpyridin-3-yl)-1H- pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)pyrimidin-2-amine

LCMS found 640.3 251 5-Chloro-4-(1-(6-((4- isopropylpiperazin-1-yl)methyl)-2- methylpyridin-3-yl)-1H- pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)pyrimidin-2-amine

LCMS found 654.3 252 N-(1-((1-Methyl-1H- imidazol-4-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-6-((4- methylpiperazin-1-yl)methyl)pyridin-3-yl)- 1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 660.3 253 4-(1-(6-((4- Ethylpiperazin-1- yl)methyl)-2-methylpyridin-3-yl)-1H- pyrazol-4-yl)-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 674.3 254 4-(1-(6-((4- Isopropylpiperazin-1- yl)methyl)-2-methylpyridin-3-yl)-1H- pyrazol-4-yl)-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 688.4 255 N-((3R,4S)-3-methyl-1- ((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-6-((4- methylpiperazin-1-yl)methyl)pyridin-3-yl)- 1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 674.3 256 4-(1-(6-((4- Ethylpiperazin-1- yl)methyl)-2-methylpyridin-3-yl)-1H- pyrazol-4-yl)-N-((3R,4S)- 3-methyl-1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 688.4 257 4-(1-(6-((4- Isopropylpiperazin-1- yl)methyl)-2-methylpyridin-3-yl)-1H- pyrazol-4-yl)-N-((3R,4S)- 3-methyl-1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 702.3

Example 258.4-(1-(2-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

Step 1: tert-Butyl4-((4-(1-(2-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate

To a mixture of tert-butyl4-((4-(1-(2-chloro-4-formylphenyl)-1H-pyrazol-4-yl)-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 34, 100 mg, 0.197 mmol) in 1,2-dichloroethane (0.5 mL) wasadded 1-methylpiperazine (39.4 mg, 0.394 mmol) andN-ethyl-N-isopropylpropan-2-amine (68.8 μL, 0.395 mmol) and the reactionmixture was stirred at r.t. for 30 minutes before sodiumtriacetoxyborohydride (125 mg, 0.591 mmol) was added and the reactionmixture was stirred at r.t. overnight. The reaction mixture was thenconcentrated, and the crude residue was then purified by silica gelflash column chromatography (eluting with a gradient of 0 to 10%MeOH/CH₂C₁₋₂). LCMS calculated for C₃₀H₃₉ClN₉O₂(M+H)⁺: m/z=592.3; Found592.2.

Step 2:4-(1-(2-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

To a mixture of tert-butyl4-((4-(1-(2-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate(from Step 1, 20 mg, 0.034 mmol) in CH₂Cl₂ (2 mL) was added a 4 molarsolution of HCl in 1,4-dioxane (33.8 μL, 0.135 mmol) and the reactionmixture was stirred at r.t. for 1 hour. The mixture was thenconcentrated, and to the residue was added CH₂Cl₂ (2 mL), followed bypyridine-2-sulfonyl chloride (12 mg, 0.068 mmol) and triethylamine (14μL, 0.10 mmol), and the reaction mixture was stirred at r.t. for 2hours. The reaction mixture was then concentrated, and to the cruderesidue was added methanol/water (5:1, v/v) and the mixture was purifiedwith prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₃₀H₃₄ClN₁₀O₂S (M+H)⁺: m/z=633.2; Found 633.2.

TABLE 19 The compounds in Table 19 were prepared in accordance with thesynthetic protocols set forth in Example 258 using the appropriatestarting materials. Ex. Name Structure Analytical data 2594-(1-(2-Chloro-4-((4- methylpiperazin-1- yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1- (cyclopropylsulfonyl) piperidin-4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 596.3 260 4-(1-(2-Chloro-4-((4- methylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-((1- methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 636.2 261 4-(1-(2-Chloro-4-((4- methylpiperazin-1-yl)methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 636.2

Example 262.4-(1-(6-((tert-Butylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

To a mixture of4-(1-(6-formyl-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Intermediate 33, 20 mg, 0.043 mmol) in CH₂Cl₂ (0.5 mL) was added2-methylpropan-2-amine (9.4 mg, 0.13 mmol) andA-ethyl-A-isopropylpropan-2-amine (15 μL, 0.086 mmol) and the reactionmixture was stirred at r.t. for 30 minutes before sodiumtriacetoxyborohydride (27.3 mg, 0.129 mmol) was added and the reactionmixture was stirred at r.t. overnight. The reaction mixture was thenconcentrated, and to the crude residue was added methanol/water (5:1,v/v) and the mixture was purified with prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₅H₃₄N₉O₂S (M+H)⁺:m/z=524.3; Found: 524.3.

TABLE 20 The compounds in Table 20 were prepared in accordance with thesynthetic protocols set forth in Example 262 using the appropriatestarting materials. Ex. Name Structure Analytical data 263 4-(1-(6-(((2-Cyclopropylpropan-2- yl)amino)methyl)-2- methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1- (methylsulfonyl)piperidin- 4-yl)amino)pyrimidine-5-carbonitrile

LCMS found 550.3 264 2-(((5-(4-(5-Cyano-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-6- methylpyridin-2- yl)methyl)amino)-2-methylpropanamide

LCMS found 553.2 265 4-(1-(6-(((1s,3s)-3- Hydroxy-1-methylcyclobutyl)amino) methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2- ((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 552.2

TABLE 21 The compounds in Table 21 were prepared in accordance with thesynthetic protocols set forth in Example 112 using the appropriatestarting materials. Ex. Name Structure Analytical data 2665-Chloro-N-(1-((1- methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-6- ((methylamino)methyl) pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine

LCMS found 557.2 267 5-Chloro-4-(1-(6- ((ethylamino)methyl)-2-methylpyridin-3-yl)-1H- pyrazol-4-yl)-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)pyrimidin-2-amine

LCMS found 571.2 268 N-(1-((1-Methyl-1H- imidazol-4-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-6- ((methylamino)methyl)pyridin-3-yl)-1H-pyrazol-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 591.2 269 4-(1-(6- ((Ethylamino)methyl)-2-methylpyridin-3-yl)-1H- pyrazol-4-yl)-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 605.2 270 N-((3R,4S)-3-Methyl-1- ((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)-4-(1-(2-methyl-6- ((methylamino)methyl)pyridin-3-yl)-1H-pyrazol-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 605.2 271 4-(1-(6- ((Ethylamino)methyl)-2-methylpyridin-3-yl)-1H- pyrazol-4-yl)-N-((3R,4S)- 3-methyl-1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 619.3 272 2-(((3R,4S)-3-Methyl-1- ((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)amino)-4-(1-(2- methyl-6-((methylamino)methyl) pyridin-3-yl)-1H-pyrazol-4- yl)pyrimidine-5-carbonitrile

LCMS found 562.3 273 4-(1-(6- ((Ethylamino)methyl)-2-methylpyridin-3-yl)-1H- pyrazol-4-yl)-2-(((3R,4S)-3-methyl-1-((1-methyl- 1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 576.3

TABLE 22 The compounds in Table 22 were prepared in accordance with thesynthetic protocols set forth in Example 151 using the appropriatestarting materials. Ex. Name Structure Analytical data 2745-Chloro-4-(1-(6- ((isopropylamino)methyl)- 2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-(1- ((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)pyrimidin-2-amine

LCMS found 585.2 275 4-(1-(6- ((Isopropylamino)methyl)-2-methylpyridin-3-yl)- 1H-pyrazol-4-yl)-N-(1- ((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 619.3 276 4-(1-(6- ((Isopropylamino)methyl)-2-methylpyridin-3-yl)- 1H-pyrazol-4-yl)-N- ((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 633.3 277 4-(1-(6-((tert- Butylamino)methyl)-2-methylpyridin-3-yl)-1H- pyrazol-4-yl)-2-((1- (cyclopropylsulfonyl)piperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 550.3 278 4-(1-(6- ((Isopropylamino)methyl)-2-methylpyridin-3-yl)- 1H-pyrazol-4-yl)-2- (((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4- yl)amino)pyrimidine-5-carbonitrile

LCMS found 590.3

TABLE 23 The compounds in Table 23 were prepared in accordance with thesynthetic protocols set forth in Example 166 using the appropriatestarting materials. Ex. Name Structure Analytical data 279 Methyl((1R,3R)-3-((3- chloro-4-(4-(5-cyano-2- ((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4- yl)-1H-pyrazol-1- yl)benzyl)amino)cyclopentyl)carbamate

LCMS found 628.2 280 Methyl ((1S,3R)-3-((3- chloro-4-(4-(5-cyano-2- ((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidin-4- yl)-1H-pyrazol-1-yl)benzyl)amino) cyclopentyl)carbamate

LCMS found 628.2 281 Methyl ((1,S,2S)-2-((3- chloro-4-(4-(5-cyano-2- (1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidin-4- yl)-1H-pyrazol-1-yl)benzyl)amino) cyclopentyl)carbamate

LCMS found 628.3 282 Methyl ((1-((3-chloro-4- (4-(5-cyano-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidin-4- yl)-1H-pyrazol-1-yl)benzyl)amino) cyclopentyl)methyl) carbamate

LCMS found 642.3

TABLE 24 The compounds in Table 24 were prepared in accordance with thesynthetic protocols set forth in Example 173 using the appropriatestarting materials. Ex. Name Structure Analytical data 2834-(1-(2-Chloro-4- ((((1s,4s)-4-hydroxy-4- methylcyclohexyl)amino)methyl)phenyl)-1H- pyrazol-4-yl)-2-((1- (cyclopropylsulfonyl)piperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 625.3 284 4-(1-(2-Chloro-4- ((((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(cyclopropylsulfonyl) piperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 625.3 285 4-(1-(2-Chloro-4- ((((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(cyclopropylsulfonyl) piperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 597.3 286 4-(1-(2-Chloro-4- ((((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(cyclopropylsulfonyl) piperidin-4- yl)amino)pyrimidine-5- carbonitrile

LCMS found 597.3 287 (±)-4-(1-(2-Chloro-4- ((((1r,2r)-2-hydroxy-2-methylcyclohexyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin- 4-yl)amino)pyrimidine-5- carbonitrile

LCMS found 613.3 288 4-(1-(2-Chloro-4- ((((1R,2S)-2-hydroxycyclohexyl)amino) methyl)phenyl)-1H- pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 599.2 289 4-(1-(2-chloro-4- ((((1s,4s)-4-(hydroxymethyl)cyclohexyl) amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 599.2 290 4-(1-(2-Chloro-4-(((2- (1,1- dioxidothiomorpholino)ethyl)amino)methyl)phenyl)- 1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 648.2

TABLE 25 The compounds in Table 25 were prepared in accordance with thesynthetic protocols set forth in Example 157 using the appropriatestarting materials. Ex. Name Structure Analytical data 291(R)-4-(1-(2-Chloro-4- (((2- hydroxypropyl)amino)methyl)phenyl)-1H-pyrazol- 4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 545.2 292 (S)-4-(1-(2-Chloro-4-(((2- hydroxypropyl)amino)methyl)phenyl)-1H-pyrazol- 4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine- 5-carbonitrile

LCMS found 545.2

Example A1. CDK2/Cyclin E1 HERE Enzyme Activity Assay

CDK2/Cyclin E1 enzyme activity assays utilize full-length human CDK2co-expressed as N-terminal GST-tagged protein with FLAG-Cyclin E1 in abaculovirus expression system (Cama Product Number 04-165). Assays areconducted in white 384-well polystyrene plates in a final reactionvolume of 8 μL. CDK2/Cyclin E1 (0.25 nM) is incubated with compounds (40nL serially diluted in DMSO) in the presence of ATP (50 μM or 1 mM) and50 nM ULight™-labeled eIF4E-binding protein 1 (THR37/46) peptide(PerkinElmer) in assay buffer (containing 50 mM HEPES pH 7.5, 1 mM EGTA,10 mM MgCl₂, 2 mM DTT, 0.05 mg/ml BSA, and 0.01% Tween 20) for 60minutes at room temperature. The reactions are stopped by the additionof EDTA and Europium-labeled anti-phospho-4E-BP1 antibody (PerkinElmer),for a final concentration of 15 mM and 1.5 nM, respectively. HTRFsignals are read after 1 hour at room temperature on a PHERAstar FSplate reader (BMG Labtech). Data is analyzed with IDBS XLFit andGraphPad Prism 5.0 software using a three or four parameter doseresponse curve to determine IC₅₀ for each compound. The IC₅₀ data asmeasured for the Examples at 1 mM ATP in the assay of Example A1 isshown in Table 1.

TABLE 1 Example IC₅₀ (nM) 1 + 2 + 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10 + 11 +12 + 13 + 14 + 15 ++ 16 ++ 17 + 18 ++ 19 ++++ 20 ++++ 21 + 22 + 23 +24 + 25 + 26 + 27 + 28 + 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 + 37 +38 + 39 + 40 + 41 + 42 + 43 + 44 + 45 + 46 + 47 + 48 + 49 + 50 + 51 +52 + 53 + 54 + 55 + 56 + 57 + 58 + 59 + 60 + 61 + 62 + 63 + 64 + 66 +67 + 68 + 69 + 70 + 71 + 72 + 73 + 74 + 75 + 76 + 77 + 78 + 79 + 80 +81 + 82 + 83 + 84 + 85 + 86 + 87 + 88 (peak 1) + 88 (peak 2) + 89(peak 1) + 89 (peak 2) + 90 (peak 1) + 90 (peak 2) + 91 (peak 1) + 91(peak 2) + 92 + 93 + 94 + 95 + 96 + 97 + 98 + 99 + 100 + 101 + 102 +103 + 104 + 105 + 106 + 107 + 108 + 109 + 110 + 111 + 112 + 113 + 114 +115 + 116 + 117 + 118 + 119 + 120 + 121 + 122 + 123 + 124 + 125 + 126 +127 + 128 + 129 + 130 + 131 + 132 + 133 + 134 + 135 + 136 + 137 + 138 +139 + 140 + 141 + 142 + 143 + 144 + 145 + 146 + 147 + 148 + 149 + 150 +151 + 152 + 153 + 154 + 155 + 156 + 157 + 158 + 159 + 160 + 161 + 162 +163 + 164 + 165 + 166 + 167 + 168 + 169 + 170 + 171 + 172 + 173 + 174 +175 + 176 + 177 + 178 + 179 + 180 + 181 + 182 + 183 + 184 + 185 + 186 +187 + 188 + 189 + 190 + 191 + 192 + 193 + 194 + 195 + 196 + 197 + 198 +199 + 200 + 201 + 202 + 203 + 204 + 205 + 206 + 207 + 208 + 209 + 210 +211 + 212 + 213 + 214 + 215 + 216 + 217 + 218 + 219 + 220 + 221 + 222 +223 + 224 + 225 + 226 + 227 + 228 + 229 + 230 + 231 + 232 + 233 + 234 +235 + 236 + 237 + 238 + 239 + 240 + 241 + 242 + 243 + 244 + 245 + 246 +247 + 248 + 249 + 250 + 251 + 252 + 253 + 254 + 255 + 256 + 257 + 258 +259 + 260 + 261 + 262 + 263 + 264 + 265 + 266 + 267 + 268 + 269 + 270 +271 + 272 + 273 + 274 + 275 + 276 + 277 + 278 + 279 + 280 + 281 + 282 +283 + 284 + 285 + 286 + 287 + 288 + 289 + 290 + 291 + 292 + +refers to≤50 nM ++refers to >50 nM to 200 nM +++refers to >200 nM to 500 nM++++refers to >500 nM to 1000 nM

Example A2. JAK Inhibitory Activity Assay

Compounds herein were tested for inhibitory activity of JAK targetsaccording to the following in vitro assay described in Park et al.,Analytical Biochemistry 1999, 269, 94-104. The catalytic domains ofhuman JAK1 (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a.781-1124) with an N-terminal His tag were expressed using baculovirus ininsect cells and purified. The catalytic activity of JAK1 and JAK2 wasassayed by measuring the phosphorylation of a biotinylated peptide. Thephosphorylated peptide was detected by homogenous time resolvedfluorescence (HTRF). Each enzyme reaction was carried out with orwithout test compound (11-point dilution), JAK enzyme, 500 nM peptide,adenosine triphosphate (ATP; 1 mM), and 2.0% dimethyl sulfoxide (DMSO)in assay buffer (50 mM Tris (pH 7.8) buffer, 100 mM NaCl, 5 mM DTT, and0.1 mg/mL (0.01%) BSA). The peptide substrate (Biotin-EQEDEPEGDYFEWLE)was custom synthesized by Biosource International. Reactions werecarried out at room temperature for 1 hour and then stopped with 10 μL45 mM EDTA, 200 nM SA-APC, 4 nM Eu-Py20 in assay buffer (Perkin Elmer,Boston, Mass.). After incubation for 30 minutes at room temperature, theHTRF signal was measured on a PheraStar plate reader. The 50% inhibitoryconcentration (IC₅₀) was calculated as the compound concentrationrequired for inhibition of 50% of the fluorescent signal.

The compounds of Examples 1, 10-11, 23-39, 41, 44, 51, 54, 96, 99, 113,and 138 were found to have an IC₅₀ of ≥10,000 nM for JAK1 and JAK2 at 1mM ATP; and the compound of Example 42 was found to have an IC₅₀ of≥5,000 nM for JAK1 and JAK2 at 1 mM ATP.

Example B1. Characterization of Cyclin E1 in Ovarian and EndometrialCancer Cell Lines

The cyclin E1 (“CCNE1”) gene was evaluated in various ovarian andendometrial cancer cell lines (FIGS. 1A and 1B). CCNE1 was amplified inCOV318, OVCAR3 OVARY, Fu-OV1, and KLE cells, each of which displayed aCCNE1 gain of function by copy number (copy number (“CN”)>2) (FIG. 1A).In contrast, CCNE1 was not amplified in COV504, OV56, or Igrov1 cells,each of which displayed copy neutral (2) or loss of function of the gene(CN≤2). CN was obtained from the Broad Institute Cancer Cell LineEncyclopedia (“CCLE”) database (Barretina, et al., Nature, 2012.483(7391): p. 603-7, which is incorporated herein by reference in itsentirety).

Western blot analysis was performed on protein samples from COV318,OVCAR3_OVARY, Fu-OV1, KLE, COV504, OV56, and Igrov1 cells to evaluateCCNE1 protein levels. CCNE1 protein levels were higher in cell lineswith CCNE1 gain of function by copy number (CN>2; i.e., COV318, OVCAR3OVARY, Fu-OV1, and KLE cells) compared to cell lines with copy neutralor loss of function of the gene (CN≤2; i.e., COV504, OV56, and Igrov1cells).

Example B2. CDK2-Knockdown by siRNA Inhibits Proliferation inCCNE1-Amplified, but not CCNE1-Non-Amplified Human Cancer Cell Lines

The effect of CDK2-knockdown in CCNE1-amplified versusCCNE1-non-amplified cell lines was evaluated. CCNE1-amplified cell lines(Fu-OV1 and KLE) or CCNE1-non-amplified cell lines (COV504 and Igrov1)were treated with a control (“ctrl”) or CDK2-specific small interferingRNAs (“siRNAs”) (“CDK2 siRNA-1” and “CDK2 siRNA-2”) (FIGS. 2A and 2B and3A and 3B). Seventy-two hours after transfection with the siRNAs, thecells were harvested and subjected to cell cycle analysis byfluorescence activated cell sorting (“FACS”) (FIGS. 2A and 3A).Knockdown of CDK2 was confirmed by western blot (FIGS. 2B and 3B).CDK2-knockdown inhibited proliferation in CCNE1-amplified cell lines,but not in CCNE1-non-amplified cell lines (FIGS. 2A and 3A).

A similar experiment was performed in additional CCNE1-amplified celllines (COV318, OVCAR3, Fu-OV1, and KLE) and CCNE1-non-amplified celllines (COV504, OV56, and Igrov1) (FIG. 4). The percentage of cells atthe S phase three days after treatment with CDK2-specific siRNAs wassignificantly decreased in CCNE1-amplified cell lines as compared totreatment with control siRNA (FIG. 4). Consistent with the results ofFIGS. 2A and 3A, the percentage of cells at the S phase three days aftertreatment with CDK2-specific siRNAs was not significantly different inCCNE1-non-amplified cell lines as compared to treatment with controlsiRNA (FIG. 4).

Example B3. Proliferation in CCNE1 Amplified and CCNE-Non-Amp LiftedCell Lines Upon CDK4/6 Inhibition

The effect of CDK4/6-inhibition in CCNE1-amplified versusCCNE1-non-amplified cell lines was evaluated. CCNE1-amplified cells(OVCAR3) or CCNE1-non-amplified cells (COV504) were treated withdimethyl sulfoxide (“DMSO”) control or increasing concentrations ofCDK4/6 inhibitor palbociclib (FIG. 5). Sixteen hours after treatmentwith DMSO or palbociclib, the cells were harvested and subjected to cellcycle analysis by FACS (FIG. 5). CDK4/6-inhibition resulted indose-dependent inhibition of the proliferation in CCNE1-non-amplifiedcells, but not in CCNE1-amplified cells (FIG. 5).

A similar experiment was performed in a larger set of CCNE1-amplifiedcell lines (COV318 and OVCAR3) and CCNE1-non-amplified cell lines(COV504, OV56, and Igrov1) (FIG. 6). The percentage of cells at the Sphase 16 hours after treatment with palbociclib was decreased inCCNE1-non-amplified cell lines in a dose-dependent fashion as comparedto treatment with DMSO (FIG. 6). Consistent with the results of FIG. 5,the percentage of cells at the S phase 16 hours after treatment withpalbociclib was not significantly different in CCNE1-amplified celllines as compared to treatment with DMSO (FIG. 6).

Example B4. CDK2-Knockdown Blocks Rb Phosphorylation at S780 inCCNE1-Amplified, but not in CCNE1-Non-Amplified, Cell Lines

The effect of CDK2-knockdown on Rb phosphorylation at Ser-780 of SEQ IDNO:3 (“S780”) in CCNE1-amplified versus CCNE1-non-amplified cell lineswas evaluated. CCNE1-amplified cell lines (COV318, Fu-OV1 and KLE) orCCNE1-non-amplified cell lines (COV504, OV56 and Igrov1) were treatedwith Ctrl or CDK2-specific siRNAs (FIGS. 7A and 7B). 72 hours aftertransfection with the siRNAs, the cells were harvested and total proteinwas extracted and analyzed by western blot. Knockdown of CDK2 wasconfirmed by western blot. CDK2-knockdown blocked Rb phosphorylation atS780 in CCNE1-amplified cell lines (FIG. 7A), but not inCCNE1-non-amplified cell lines (FIG. 7B).

Example B5. Palbociclib Blocks Rb Phosphorylation at S780 in CCNE1Non-Amplified, but not in CCNE1-Amplified, Cell Lines

The effect of CDK4/6-inhibition on Rb phosphorylation at S780 inCCNE1-amplified versus CCNE1-non-amplified cell lines was evaluated.CCNE1-amplified cell lines (OVCAR3 and COV318) or CCNE1-non-amplifiedcell lines (COV504 and OV56) were treated with DMSO or various doses ofpalbociclib (FIGS. 8A and 8B). One or 15 hours after treatment, thecells were harvested and total protein was extracted and analyzed bywestern blot (FIG. 8). Palbociclib treatment blocked Rb phosphorylationat S780 in CCNE1-non-amplified cell lines (FIG. 8B), but not inCCNE1-amplified cell lines (FIG. 8A).

Example B6. CDK2 Degradation by dTAG Decreases Rb Phosphorylation atS780

To further confirm that CDK2 knockdown decreases Rb phosphorylation atS780 in CCNE1-amplified cells (see Example B4), the dTAG system was usedto degrade CDK2 and the level of S780-phosphorylated Rb was evaluated(Erb et al., Nature, 2017, 543(7644):270-274, which is incorporatedherein by reference in its entirety). Briefly, OVCAR3 cells wereengineered to express Cas9 by lentiviral transduction of Cas9 construct.The OVCAR3-Cas9 cells were then engineered to express CDK2-FKBP12F36V-HAfusion protein by lentiviral transduction of CDK2-FKBP12F36V-HAexpression construct. Next, to engineer the line to have endogenous CDK2inactivated, OVCAR3 (Cas9, CDK2-FKBP12F36V-HA) cells were transducedwith CDK2 sgRNA (“CDK2-gRNA”); OVCAR3 (Cas9, CDK2-FKBP12F36V-HA) cellstransduced with non-targeting sgRNA (“Ctl-gRNA”; Cellecta) served as acontrol cell line.

To degrade CDK2-FKBP12F36V-HA protein by dTAG (FIG. 9A), cells weretreated with DMSO or with a titration of concentrations of dTAG for 14hours. Cells were collected and processed for Western blot (FIG. 9B). Adose-responsive degradation of CDK2-FKBP12(F36V) was detected by westernblot after treatment with dTAG in both control- and CDK2-gRNA treatedcells (FIG. 9B). Degradation was further confirmed by western blot forHA-Tag. Endogenous CDK2 protein was detected in OVCAR3 cells treatedwith control gRNA, but not with CDK2-gRNA (FIG. 9B). CDK2-FKBP12(F36V)degradation inhibited Rb phosphorylation at S780 in CDK2 knockout OVCAR3cells, but not in OVCAR3 cells with endogenous CDK2 expression.

Example B7. p-Rb S780 HTRF Cellular Assay for Identification of CDK2Inhibitors

An in vitro CDK2/CCNE1 enzyme activity assay was used to measurephosphorylation of a peptide substrate using homogenous time-resolvedenergy transfer (“HTRF”). First, the specificity of8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound A; see US Patent Application Publication No. 2018/0044344 atpage 51, paragraph [0987], which is incorporated by reference herein inits entirety) for CDK2 inhibition was confirmed via a kinase activityassay (FIG. 10A). To this end, the LANCE® Ultra kinase assay was usedwith a ULight™-labeled EIF4E-binding protein 1 (Thr37/46) peptide(PerkinElmer, TRF0128-M) as substrate and an Europium-labeledanti-phospho-EIF4E binding protein1 (Thr37/46) antibody (PerkinElmer,TRF0216-M). A ratio of fluorescence transferred to the labeled substrate(665 nm) relative to fluorescence of the Europium donor (620 nm)represents the extent of phosphorylation. The IC₅₀ for Compound A wasdetermined to be 1.1 nM (FIG. 10A). In contrast, the IC₅₀ for the CDK4/6inhibitor palbociclib was 10,000 nM (FIG. 10A).

Next, a CDK2 pRb (S780) HTRF cellular assay was performed, enabling thequantitative detection of Rb phosphorylated on serine 780 in CCNE1amplified COV318 cells upon treatment with Compound A or palbociclib(FIG. 10B). Treatment with Compound A, but not palbociclib, inhibited Rbphosphorylation on serine 780 in CCNE1 amplified cells (FIG. 10B). TheIC₅₀ for Compound A in this assay was 37 nM, while the IC₅₀ forpalbociclib was >3,000 nM (FIG. 10B).

Example B8. Bioinformatics Analysis of CCLE Dataset Reveals theSensitivity to CDK2 Inhibition in CCNE1 Amplified Cells Relies onFunctional p16

In an attempt to identify a biomarker for predicting sensitivity toCDK2-inhibition in CCNE1-amplified cells, 460 cell lines from CCLE wereanalyzed (Barretina, supra). First, the cell lines were filtered basedon CCNE1 copy number and expression and CDK2 sensitive score based onshRNA knockdown data. A total of 41 cell lines were identified as havingCCNE1 copy number of >3 and CCNE1 expression score (CCLE: >3). Of these41 cell lines, 18 (44%) were sensitive to CDK2 inhibition (CDK2sensitive score≤−3), while 23 (56%) were insensitive to CDK2 inhibition(CDK2 sensitive score>−3).

Next, the p16 status was evaluated in the CDK2-sensitive andCDK2-insensitive cell lines (FIG. 11). Of the 18 cell lines that weresensitive to CDK2-inhibition, 100% expressed normal p16 gene (FIG. 11).In contrast, only 4 of the 23 CDK2-insensitive cell lines expressednormal p16 gene (FIG. 11). The majority of the 23 CDK2-insensitive celllines displayed dysfunctional p16 gene expression: the p16 gene wasdeleted in 10 of 23 cell lines; the p16 gene was silenced in 5 of the 23cell lines, and the p16 gene was mutated in 4 of the 23 cell lines (FIG.11).

A summary of CDK2 sensitivity and CDKN2A/p16 status in CCNE1 amplifiedcell lines is provided in Table 18, below.

TABLE 18 Cell lines with CDK2 sensitive Score ≤ 3 counted as CDK2Sensitive lines; ≥3 as CDK2 insensitive line. Cell lines verified inexperiments are in bold. NCIN87_STOMACH showed no CDKN2A/P16 proteinexpression in western blot. CCNE1 and CDKN2A/P16 copy number werecalculated based on CCLE dataset. Expression Score < 0 counted as genesilencing. CDKN2A/ CDK2 CCNE1 CDKN2 p16 mRNA CDKN2a/ sensitive Copy ACopy Expression p16 Cell Lines Score No. No. Score DysfunctionHCC1569_BREAST −9.6 16 2 5.11 OVISE_OVARY −9.4 3 2 4.17 MKN1_STOMACH−8.9 5 1 4.28 EFE184_ENDOMETRIUM −8.7 3 2 3.97 KURAMOCHI_OVARY −8.2 3 23.60 MKN7_STOMACH −7.7 21 1 4.37 MDAMB157_BREAST −7.6 6 2 5.01HCC70_BREAST −7.6 4 4 4.88 NIHOVCAR3_OVARY −7.4 10 2 4.15 FUOV1_OVARY −710 3 5.19 KLE_ENDOMETRIUM −7 7 2 6.24 COV318_OVARY −7 14 2 5.09CAOV4_OVARY −6.7 3 2 3.59 MFE280_ENDOMETRIUM −6.3 4 2 4.97 NCIH661_LUNG−6.2 5 2 3.73 OVCAR4_OVARY −4.3 4 1 4.77 SNU8_OVARY −3.8 5 3 5.35OVCAR8_OVARY −3.7 3 2 5.21 RMUGS_OVARY −2.8 4 1 −0.08 SilencingNCCSTCK140_STOMACH −2.7 3 0 −4.70 Deletion NCIH2286_LUNG −1.6 3 1 3.63Mutation HOP62_LUNG −1.4 4 0 −1.21 Deletion LN340_CENTRAL_NERVOUS_ −1.03 0 −5.47 Deletion SYSTEM NCIH1339_LUNG −0.8 3 2 2.42 UnknownNCIN87_STOMACH 0.1 3 2 4.67 No preteen U2OS_BONE 0.4 3 1 −5.72 SilencingSF172_CENTRAL_NERVOUS_ 0.5 3 0 −2.35 Deletion SYSTEM CAL120_BREAST 0.6 41 4.86 RMGI_OVARY 0.9 3 0 −3.33 Deletion OV90_OVARY 0.9 3 1 3.95Mutation SNU601_STOMACH 1.1 4 2 −3.79 Silencing EW8_BONE 1.5 5 1 3.11JHESOAD1_OESOPHAGUS 1.7 5 0 −5.52 Deletion HCC1806_BREAST 1.9 8 0 −4.61Deletion NCIH2170_LUNG 2.0 3 0 −3.73 Deletion HCC1428_BREAST 2.3 3 22.28 A549_LUNG 2.5 4 0 −6.13 Deletion LXF289_LUNG 2.6 4 3 4.10 MutationAGS_STOMACH 3.0 3 2 −5.56 Silencing NCIH647_LUNG 3.0 4 0 −5.07 DeletionHLF_LIVER 3.9 3 2 3.40

Example B9. CCNE1 Amplified Cells with Dysfunctional p16 do not Respondto CDK2 Inhibition

To further evaluate the role of p16 in CDK2-sensitivity inCCNE1-amplified cells, p16 protein expression in three gastric celllines with CCNE1-amplification was evaluated by western blot. AGS andNCI-N87 cells displayed absent or dramatically reduced levels of p16(FIG. 12A). In contrast, p16 protein was detected in MKN1 cellularprotein extracts (FIG. 12A).

Next, the impact of CDK2-knockdown in these cells was evaluated. Mkn1,Ags, and NCI-N87 cells were treated with control or CDK2-specific siRNA.Three days-post-siRNA transfection, cell cycle phase distribution of thecells was evaluated by FACS. The percentage of cells at the S phase inthe Mkn1 cells (CCNE1-amplified, p16 protein detected) was significantlydecreased in the CDK2 siRNA-treated cells as compared to control (FIG.12B). In contrast, the percentage of cells at the S phase was notsignificantly decreased in Ags and NCI-N87 cells (CCNE1-amplified,dysfunctional p16 protein levels) after treatment with CDK2 siRNA ascompared to control (FIG. 12B).

Example B10. p16 Knockdown by siRNA Abolishes CDK2 Inhibition InducedCell Cycle Suppression in CCNE1 Amplified Cells

To confirm the role of p16 in CDK2-sensitivity of CCNE1-amplified cells,COV318 cells were treated with control or p16-specific siRNA.Seventy-two hours after transfection, cells were treated with DMSO(control) or 100 nM of Compound A. Sixteen hours after treatment withDMSO or the CDK2-inhibitor, cells were harvested and subjected to cellcycle analysis by FACS. Consistent with the results described above, thepercentage of S phase cells significantly decreased in the controlsiRNA-treated cells treated with CDK2-inhibitor (Compound A), but notwith the DMSO control (FIG. 13). In contrast, the percentage of S phasecells was not significantly decreased after treatment with theCDK2-inhibitor (Compound A) in p16 knocked down cells as compared toDMSO control (FIG. 13).

Materials and Methods Used in Examples B1-B10

Cell Culture and Transfection

Human cyclin E1 (CCNE1) amplified ovarian cell lines OVCAR3, COV318,Fu-OV1, endometrial cell line KLE, gastric cell lines MKN1, AGS, NCIN87,and CCNE1 non-amplified ovarian cell lines COV504, OV56, Igrov1 werecultured in RPMI 1640 medium. The complete growth medium wassupplemented with 10% FBS, 0.1 mM non-essential amino acids, 2 mML-glutamine, 100 units/mL penicillin G and 100 μg/mL streptomycin in 37°C. humidified incubator and an atmosphere of 5% CO₂ in air. Fu-OV1 linewas purchased from Leibniz-Institute DSMZ—German Collection ofMicroorganisms and Cell Cultures; MKN1 was purchased from JapaneseCancer Research Resources Bank; and the rest of cell lines werepurchased from American Type Culture Collection. For transfection, cellswere seeded into 6-well for 24 hours and transiently transfected byLipofectamine 2000 Reagent (Thermo Fisher, 11668027). ON-TARGETplusHuman CKD2 siRNAs (GE Healthcare Dharmacon, J-003236-11-0002 andJ-003236-12-0002) and ON-TARGETplus Human CDKN2A/p16 siRNAs (GEHealthcare Dharmacon, J-011007-08-0002) were used to knockdown theendogenous CDK2 and CDKN2A/p16. ON-TARGETplus Non-targeting Pool (GEHealthcare Dharmacon, D-001810-10-20) was used as a negative control.

Western Blot Analysis

Whole cell extracts were prepared using RIPA buffer (Thermo Scientific,89900) with a Halt Protease and Phosphatase Inhibitor Cocktail (ThermoScientific, 78440). Protein concentration was quantified with a BCAProtein Assay Kit (Thermo Scientific, 23225) and 40 μg of proteinlysates were loaded for SDS-PAGE using precast gradient gels (Bio-Rad,Hercules, No. 456-1094). Samples were diluted in 5× Laemmli buffer (300mM Tris-HCl pH 6.8, 10% SDS (w/v), 5% 2-mercaptoethanol, 25% glycerol(v/v),0.1% bromophenol blue w/v) and boiled for 5 minutes. 35 μg ofproteins were separated by 8-15% SDS-PAGE and transferred ontopolyvinylidene fluoride (PVDF) membranes. Unspecific binding sites onthe PVDF membranes were blocked with 5% non-fat milk in TEST (20 mMTris-HCl, pH 7.6, 137 mM NaCl, 1% Tween-20). Membranes were hybridizedwith antibodies against anti-CDKN2A/p16 (Cell Signaling Technology,92803S), anti-Cas9 (Cell Signaling Technology, 97982S), anti-HA (CellSignaling Technology, 3724S), anti-Rb (Cell Signaling Technology,9309S), anti-phospho-Rb (Ser780) (Cell Signaling Technology, 8180S),anti-CDK2 (Cell Signaling Technology, 2546S), anti-CCNE1 (Cell SignalingTechnology, 20808S) and anti-GAPDH (Cell Signaling Technology, 8884S)for overnight at 4° C., followed by incubation with horseradishperoxidase (HRP)-conjugated secondary antibodies for 1 hour at roomtemperature. The membranes were then developed using Immobilon Westernchemiluminescence HRP substrates (Millipore, WBKLS0500). Images werecaptured by Luminescence/Fluorescence Imaging System Odyssey CLx Imager(LI-COR).

Cell Cycle Analysis

Cells were seeded in six-well tissue culture plates and 24 hours laterwere treated with a titration of concentrations of Palbociclib orCompound A. After overnight treatment, cells exposed to 10 μM EdU for 3hours before detection of EdU-DNA by Click-iT AlexaFluor® 647 azide kit(Life Technology, C10424) following the manufacturer's instructions.Bulk DNA was stained with DAPI. Compound-treated and DMSO treatedcontrol cells were acquired with CytoFlex (Beckman Coulter) and wereanalyzed using the FlowJo software. For cell cycle analysis of cellswith siRNA knockdown, 72 hours after siRNA transfection, cells exposedto 10 μM EdU for 3 hours before detection of Click-iT Alexa Fluor® 647azide kit.

Plasmids

LentiCas9 plasmid pRCCH-CMV-Cas9-2A (Cellecta, SVC9-PS) was used forCas9 expression. sgRNA-CDK2 lentiviral construct, designed to targetAAGCAGAGATCTCTCGGA (SEQ ID NO:8) of CDK2, was cloned into sgRNAexpression vector pRSG-U6 and purchased from Cellecta (93661). ForCDK2-FKBP12F36V-HA expression, a 1306 base pair DNA fragment encodingCDK2 and FKBP12F36V-2×HA tag at the C-terminus was synthesized andcloned into EcoRI and BamHI digested pCDH-EF1α-MCS-T2A-Puro lentivector(Systembio, CD527A-1).

Sequence of 1306 bp DNA Fragment:

(SEQ ID NO: 4)    CCTCGAATTCAGCTGCATGGAGAACTTCCAAAAGGTGGAAAAGATCGGAGAGGGCACGTACGGAGTTGTGTACAAAGCCAGAAACAAGTTGACGGGAGAGGTGGTGGCGCTTAAGAAAATCCGCCTGGACACTGAGACTGAGGGTGTGCCCAGTACTGCCATCCGAGAGATCTCTCTGCTTAAGGAGCTTAACCATCCTAATATTGTCAAGCTGCTGGATGTCATTCACACAGAAAATAAACTCTACCTGGTTTTTGAATTTCTGCACCAAGATCTCAAGAAATTCATGGATGCCTCTGCTCTCACTGGCATTCCTCTTCCCCTCATCAAGAGCTATCTGTTCCAGCTGCTCCAGGGCCTAGCTTTCTGCCATTCTCATCGGGTCCTCCACCGAGACCTTAAACCTCAGAATCTGCTTATTAACACAGAGGGGGCCATCAAGCTAGCAGACTTTGGACTAGCCAGAGCTTTTGGA GT ACCTGTTCGTACTTACACCCATGA A GTGGTGACCCTGTGGTACCGAGCTCCTGAAATCCTCCTGGGCTGCAAATATTATTCCACAGCTGTGGACATCTGGAGCCTGGGCTGCATCTTTGCTGAGATGGTGACTCGCCGGGCCCTATTCCCTGGAGATTCTGAGATTGACCAGCTCTT T CGGATCTTTCGGACTCTGGGGACCCCAGATGAGGTGGTGTGGCCAGGAGTTACTTCTATGCCTGATTACAAGCCAAGTTTCCCCAAGTGGGCCCGGCAAGATTTTAGTAAAGTTGTACCTCCCCTGGATGAAGATGGACGGAGCTTGTTATCGCAAATGCTGCACTACGACCCTAACAAGCGGATTTCGGCCAAGGCAGCCCTGGCTCACCCTTTCTTCCAGGATGTGACCAAGCCAGTACCCCATCTTC GACTCGGAGTGCAGGTGGAAACCATCTCCCCAGGAGACGGGCGCACCTTCCCCAAGCGCGGCCAGACCTGCGTGGTGCACTACACCGGGATGCTTGAAGATGGAAAGAAAGTTGATTCCTCCCGGGACAGAAACAAGCCCTTTAAGTTTATGCTAGGCAAGCAGGAGGTGATCCGAGGCTGGGAAGAAGGGGTTGCCCAGATGAGTGTGGGTCAGAGAGCCAAACTGACTATATCTCCAGATTATGCCTATGGTGCCACTGGGCACCCAGGCATCATCCCACCACATGCCACTCTCGTCTTCGATGTGGAGCTTCTAAAACTGGAAGGATACCCTTACGACGTTCCTGATTACGCTTACCCTTACGACGTTCCTGATTACGCT GGATCCTAA TTCGAAAGC 

GAATTC (SEQ ID NO:5; EcoRI), GGATCC (SEQ ID NO:6; BamHI) and TTCGAA (SEQID NO:7; BstBI) restriction enzyme sites were underlined. Sequenceencoding CDK2 is in bold and sequence of FKBP12F36V-HA is in italics. 3nucleic acids underlined within CDK2 sequence indicated modificationsthat abolished PAM sites to avoided CRISPR knockout effect. Thesechanges did not change amino acids encoded.

Lentivirus Production

Production of lentivirus was performed in 293T cells by co-transfectionof Lentiviral Packaging Mix (Sigma, SHP001), and a given lentiviralexpression plasmid using Lipofectamine 2000. Viral supernatants werecollected 48 and 72 hours after transfection, filtered through a 0.22 μmmembrane. All cells lines were transduced by spinoculation at 2000revolutions per minute (rpm) for 1 hour at room temperature with 8 μg/mLpolybrene (Santa Cruz, sc-134220).

CDK2-dTAG Cells

OVCAR3 cells were first engineered to express Cas9 by lentiviraltransduction of Cas9 construct. Cells were selected and maintained in100 μg/mL hygromycin (Life Technologies, 10687010) and verified toexpress Cas9 by immunoblot. OVCAR3-Cas9 cells were then engineered toexpress CDK2-FKBP12F36V-HA fusion protein by lentiviral transduction ofCDK2-FKBP12F36V-HA expression construct and selection with 2 μg/mLpuromycin dihydrochloride (Life Technologies, A1113803). Expression ofCDK2-FKBP12F36V-HA was verified by immunoblot using anti-CDK2 andanti-HA antibodies. Next, to engineer the line to have endogenous CDK2inactivated, OVCAR3 (Cas9, CDK2-FKBP12F36V-HA) cells were transducedwith CDK2 sgRNA and selected by 50 μg/mL Zeocin (Life Technologies,R25001). Inactivated expression of endogenous CDK2 in the expandedclones was tested by immunoblotting. OVCAR3 (Cas9, CDK2-FKBP12F36V-HA)cells transduced with non-targeting sgRNA (Cellecta) were served as acontrol cell line.

To degrade CDK2-FKBP12F36V-HA protein by dTAG, 200,000 cells were seededin 1 mL media in triplicate in a 24-well plate and treated with dimethylsulfoxide (DMSO) or with a titration of concentrations of dTAG for 14hours. Cells were collected and processed for Western blot.

CDK2/CCNE1 Enzymatic Assay

In vitro CDK2/CCNE1 enzyme activity assay measures phosphorylation of apeptide substrate using homogeneous time-resolved energy transfer(HTRF). The LANCE® Ultra kinase assay used a ULight™-labeledEIF4E-binding protein 1 (Thr37/46) peptide (PerkinElmer, TRF0128-M) assubstrate and an Europium-labeled anti-phospho-EIF4E binding protein 1(Thr37/46) antibody (PerkinElmer, TRE0216-M). A ratio of fluorescencetransferred to the labeled substrate (665 nm) relative to fluorescenceof the Europium donor (620 nm) represents the extent of phosphorylation.Ratios for treated wells are normalized to DMSO only (100% activity) andno enzyme (0% activity) controls. Normalized data is analyzed using afour parameter dose response curve to determine IC₅₀ for each compound.

CDK2 pRb (S780) HTRF Cellular Assay

CDK2 pRb (S780) HTRF cellular assay enables the quantitative detectionof Rb phosphorylated on serine 780 in CCNE1 amplified COV318 cells. Theassay comprised two antibodies: Europium cryptate labeledanti-Phospho-Rb S780 antibody (donor) and d2 labeled anti-Rb antibody(acceptor). In brief, COV318 cells were seeded into the wells of 96-wellplate at a density of 25,000 per well with 9-point, 3-fold serialdiluted compounds and cultured overnight at 37 degree with 5% CO₂. Thefinal concentrations of compounds start from 3 μM. The next day cellswere lysed in 70 μL 1× Phospho-total protein lysis buffer #2 (Cisbio),supplemented with 0.7 μL blocking buffer (Cisbio) and 1.4 μL proteaseinhibitor cocktail set III, EDTA-free (Calbiochem, 539134). 16 μL ofcell lysates were mixed with 4 μL of the fluorophore-conjugatedantibodies to a final concentration of 0.188 nM cryptate-labeledanti-Phospho-Rb S780 antibody and 0.14 nM d2 labeled anti-Rb antibody.After 2h of incubation at room temperature, HTRF signals were measuredon the PHERAstar microplate reader (BMG Labtech), using 340 nm asexcitation wavelength, a 620 nm filter for the Europium donorfluorescence, and a 665-nm filter for the acceptor fluorescencedetection. HTRF signals were calculated as the HTRF ratio (ratio offluorescence measured at 665 nm and 620 nm)×10000.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, 3, 4,5, or 6; o is 1, 2, 3, or 4; p is 1, 2, 3, or 4; R¹ is selected fromhalo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, andC₃₋₄ cycloalkyl; and R² is selected from H, D, halo, CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₃₋₄ cycloalkyl; or R¹is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₃₋₄ cycloalkyl; and R² is selected fromhalo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, andC₃₋₄ cycloalkyl; R³ is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl; wherein said C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(3A) substituents; R⁴ is selected from C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₄ cycloalkyl, 4-14 membered heterocycloalkyl,5-14 membered heteroaryl, C₃₋₁₄ cycloalkyl-C₁₋₆ alkyl, 6-14 memberedaryl-C₁₋₆ alkyl, 4-14 membered heterocycloalkyl-C₁₋₆ alkyl, 5-14membered heteroaryl-C₁₋₆ alkyl, (R^(4A))_(o)-6-10 membered aryl-, and(R⁶)_(p)—C₁₋₆ alkyl-; wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₄ cycloalkyl, 4-14 membered heterocycloalkyl, 5-14membered heteroaryl, C₃₋₁₄ cycloalkyl-C₁₋₆ alkyl, 6-14 memberedaryl-C₁₋₆ alkyl, 4-14 membered heterocycloalkyl-C₁₋₆ alkyl, and 5-14membered heteroaryl-C₁₋₆ alkyl are each optionally substituted by 1, 2,3, 4, 5, or 6 independently selected R^(4A) substituents; each R⁵ isindependently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a5), SR^(a5), NHOR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)NR^(c5)(OR^(a5)), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))R^(b5), NR^(c5)S(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)(═NR^(e5))R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),S(O)₂NR^(c5)R^(d5), OS(O)(═NR^(e5))R^(b5), OS(O)₂R^(b5),S(O)(═NR^(e5))R^(b5), SF₅, P(O)R^(f5)R^(g5), OP(O)(OR^(h5))(OR^(i5)),P(O)(OR^(h5))(OR^(i5)), and BR^(j5)R^(k5), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 memberedaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents; each R⁶ is independently selected from CN, NO₂,OR^(a4), SR^(a4), NHOR^(a4), C(O)R^(b4)C(O)NR^(c4)R^(d4),C(O)NR^(c4)(OR^(a4)), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))R^(b4), NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)(═NR^(e4))R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),S(O)₂NR^(c4)R^(d4), OS(O)(═NR^(e4))R^(b4), OS(O)₂R^(b4),S(O)(═NR^(e4))R^(b4), SF₅, P(O)R^(f4)R^(g4), OP(O)(OR^(h4))(OR^(i4)),P(O)(OR^(h4))(OR^(i4)), and BR^(j4)R^(k4); Ring moiety A is 4-14membered heterocycloalkyl, wherein Ring moiety A is attached to the —NH—group of Formula (I) at a ring member of a saturated or partiallysaturated ring of said 4-14 membered heterocycloalkyl; each R^(3A) isindependently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a3), SR^(a3), NHOR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)NR^(c3)(OR^(a3)), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))R^(b3), NR^(c3)S(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)(═NR^(e3))R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),S(O)₂NR^(c3)R^(d3), OS(O)(═NR^(e3))R^(b3), OS(O)₂R^(b3),S(O)(═NR^(e3))R^(b3), SF₅, P(O)R^(f3)R^(g3), OP(O)(OR^(h3))(OR^(i3)),P(O)(OR^(h3))(OR^(i3)), and BR^(j3)R^(k3), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 memberedaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents; each R^(4A) is independently selected from halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, OR^(a4), SR^(a4), NHOR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)NR^(c4)(OR^(a4)), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))R^(b4),NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)(═NR^(e4))R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4),OS(O)(═NR^(e4))R^(b4), OS(O)₂R^(b4), S(O)(═NR^(e4))R^(b4), SF₅,P(O)R^(f4)R^(g4), OP(O)(OR^(h4))(OR^(i4)), P(O)(OR^(h4))(OR^(i4)), andBR^(j4)R^(k4), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,6-10 membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4B)substituents; each R^(4B) is independently selected from H, D, halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)NR^(c41)(OR^(a41)), C(O)OR^(a41), OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),C(═NR^(e41))R^(b41), C(═NR^(e41))NR^(c41)R^(d41),NR^(c41)C(═NR^(e41))NR^(c41)R^(d41), NR^(c41)C(═NR^(e41))R^(b41),NR^(c41)S(O)NR^(c41)R^(d41), NR^(c41)S(O)R^(b41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)(═NR^(e41))R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41),S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41), S(O)₂NR^(c41)R^(d41),OS(O)(═NR^(e41))R^(b41), OS(O)₂R^(b41), S(O)(═NR^(e41))R^(b41), SF₅,P(O)R^(f41)R^(g41), OP(O)(OR^(h41))(OR^(i41)), P(O)(OR^(h41))(OR^(i41)),and BR^(j41)R^(k41), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(4C) substituents; each R^(4C) isindependently selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a42), SR^(a42), NHOR^(a42),C(O)R^(b42), C(O)NR⁴²R⁴², C(O)NR^(c42)(OR^(a42)), C(O)OR^(a42),OC(O)R^(b42), OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42),NR^(c42)NR^(c42)R^(d42), NR^(c42)C(O)R^(b42), NR⁴²C(O)OR^(a42),NR^(c42)C(O)NR^(c42)R^(d42), C(═NR^(e42))R^(b42),C(═NR^(e42))NR^(c42)R^(d42), NR^(c42)C(═NR^(e42))NR^(c42)R^(d42),NR^(c42)C(═NR^(e42))R^(b42), NR^(c42)S(O)NR^(c42)R^(d42),NR^(e42)S(O)R^(b42), NR^(c42)S(O)₂R^(b42), NR⁴²S(O)(═NR^(e42))R^(b42),NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)R^(b42), S(O)NR^(c42)R^(d42),S(O)₂R^(b42), S(O)₂NR^(c42)R^(d42), OS(O)(═NR^(e42))R^(b42),OS(O)₂R^(b42), S(O)(═NR^(e42))R^(b42), SF₅, P(O)R^(f42)R^(g42),OP(O)(OR^(h42))(OR^(i42)), P(O)(OR^(h42))(OR^(i42)), andBR^(j42)R^(k42), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(G) substituents; each R^(5A) is independentlyselected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a51), SR^(a51), NHOR^(a51),C(O)R^(b51), C(O)NR^(c51)R^(d51), C(O)NR^(c51)(OR^(a51)), C(O)OR^(a51),OC(O)R^(b51), OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51),NR^(c51)NR^(c51)R^(d51), NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51),NR^(c51)C(O)NR^(c51)R^(d51), C(═NR^(e51))R^(b51),C(═NR^(e51))NR^(c51)R^(d51), NR^(c51)C(═NR^(e51))NR^(c51)R^(d51),NR^(c51)C(═NR^(e51))R^(b51), NR^(c51)S(O)NR^(c51)R^(d51),NR^(c51)S(O)R^(b51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)(═NR^(e51))R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51),S(O)R^(b5), S(O)NR^(c51)R^(d51), S(O)₂R^(b51), S(O)₂NR^(c51)R^(d51),OS(O)(═NR^(e51))R^(b51), OS(O)₂R^(b51), S(O)(═NR^(e51))R^(b51), SF₅,P(O)R^(f51)R^(g51), OP(O)(OR^(h51))(OR^(i51)), P(O)(OR^(h51))(OR^(i51)),and BR^(j51)R^(k51), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(5B) substituents; each R^(5B) isindependently selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered hetero aryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a52), SR^(a52), NHOR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)NR^(c52)(OR^(a52)), C(O)OR^(a52), OC(O)R^(b52),OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52), NR^(c52)NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), NR^(c52)C(O)OR^(a52), NR^(c52)C(O)NR^(c52)R^(d52),C(═NR^(e52))R^(b52), C(═NR^(e52))NR^(c52)R^(d52),NR^(c52)C(═NR^(e52))NR^(c52)R^(d52), NR^(c52)C(═NR^(e52))R^(b52),NR^(c52)S(O)NR^(c52)R^(d52), NR^(c52)S(O)R^(b52), NR^(c52)S(O)₂R^(b52),NR^(c52)S(O)(═NR^(e52))R^(b52), NR^(c52)S(O)₂NR^(c52)R^(d52),S(O)R^(b52), S(O)NR^(c52)R^(d52), S(O)₂R^(b52), S(O)₂NR^(c52)R^(d52),OS(O)(═NR^(e52))R^(b52), OS(O)₂R^(b52), S(O)(═NR^(e52))R^(b52), SF₅,P(O)R^(f52)R^(g52), OP(O)(OR^(h52))(OR^(i52)), P(O)(OR^(h52))(OR^(i52)),and BR^(j52)R^(k52), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(G) substituents; each R^(a3),R^(c3), and R^(d3) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 memberedaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(G) substituents; or, any R^(c3) andR^(d3) attached to the same N atom, together with the N atom to whichthey are attached, form a 5- or 6-membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(G) substituents; each R^(b3) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,6-10 membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl, which are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents; each R^(e3) is independently selected from H, OH, CN, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,6-10 membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl; each R^(f3) and R^(g3)are independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl; each R^(h3) and R^(i3) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl; each R^(j3) and R^(k3) is independentlyselected from OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; or any R^(j3) andR^(k3) attached to the same B atom, together with the B atom to whichthey are attached, form a 5- or 6-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; each R^(a4), R^(c4), andR^(d4) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(4B) substituents; or, any R^(c4)and R^(d4) attached to the same N atom, together with the N atom towhich they are attached, form a 5- or 6-membered heteroaryl or a 4-10membered heterocycloalkyl group, wherein the 5- or 6-membered heteroarylor 4-10 membered heterocycloalkyl group is optionally substituted with1, 2, 3, or 4 independently selected R^(4B) substituents; each R^(b4) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,6-10 membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl, which are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(4B)substituents; each R^(e4) is independently selected from H, OH, CN, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,6-10 membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl; each R^(f4) and R^(g4)are independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl; each R^(h4) and R^(i4) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl; each R^(j4) and R^(k4) is independentlyselected from OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; or any R^(j4) andR^(k4) attached to the same B atom, together with the B atom to whichthey are attached, form a 5- or 6-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; each R^(a41), R^(c41), andR^(d41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(4C) substituents; or, any R^(c41)and R^(d41) attached to the same N atom, together with the N atom towhich they are attached, form a 5- or 6-membered heteroaryl or a 4-14membered heterocycloalkyl group, wherein the 5- or 6-membered heteroarylor 4-14 membered heterocycloalkyl group is optionally substituted with1, 2, 3, or 4 independently selected R^(4C) substituents; each R^(b41)is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, which are each optionally substituted with 1, 2,3, or 4 independently selected R^(4C) substituents; each R^(e41) isindependently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;each R^(f41) and R^(g41) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl; each R^(h41) and R^(i41) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;each R^(j41) and R^(k41) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy; or any R^(j41) and R^(k41) attached to the same Batom, together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; each R^(a42), R^(c42), and R^(d42) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents; or, any R^(c42) and R^(d42) attached to the same Natom, together with the N atom to which they are attached, form a 5- or6-membered heteroaryl or a 4-14 membered heterocycloalkyl group, whereinthe 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents; each R^(b42) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(G) substituents; each R^(e42) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl; each R^(f42) and R^(g42) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;each R^(h42) and R^(i42) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl; each R^(j42) and R^(k42) isindependently selected from OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; or anyR^(j42) and R^(k42) attached to the same B atom, together with the Batom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents; or, any R^(c5) and R^(d5) attached to the same Natom, together with the N atom to which they are attached, form a 5- or6-membered heteroaryl or a 4-10 membered heterocycloalkyl group, whereinthe 5- or 6-membered heteroaryl or 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents; each R^(b5) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, which are each optionally substituted with 1, 2,3, or 4 independently selected R^(5A) substituents; each R^(e5) isindependently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl; each R^(f5) and R^(g5) are independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 memberedaryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;each R^(h5) and R^(i5) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl; each R^(j5) and R^(k5) is independently selected from OH, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy; or any R^(j5) and R^(k5) attached to thesame B atom, together with the B atom to which they are attached, form a5- or 6-membered heterocycloalkyl group optionally substituted with 1,2, 3, or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; each R^(a51), R^(c51), and R^(d51) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents; or, any R^(c51) and R^(d51) attached to the same Natom, together with the N atom to which they are attached, form a 5- or6-membered heteroaryl or a 4-14 membered heterocycloalkyl group, whereinthe 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents; each R^(b51) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5B) substituents; each R^(e51) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl; each R^(f51) and R^(g51) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;each R^(h51) and R^(i51) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl; each R^(j51) and R^(k51) isindependently selected from OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; or anyR^(j51) and R^(k51) attached to the same B atom, together with the Batom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents; or, any R^(c52) and R^(d52) attached to the same Natom, together with the N atom to which they are attached, form a 5- or6-membered heteroaryl or a 4-14 membered heterocycloalkyl group, whereinthe 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents; each R^(b52) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(G) substituents; each R^(e52) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl; each R^(f52) and R^(g52) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;each R^(h52) and R^(i52) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl; each R^(j52) and R^(k52) isindependently selected from OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; or anyR^(j52) and R^(k52) attached to the same B atom, together with the Batom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;and each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.
 2. Thecompound of claim 1, having Formula (II):

or a pharmaceutically acceptable salt thereof, wherein k is n−1.
 3. Thecompound of claim 1, having Formula (III):

or a pharmaceutically acceptable salt thereof, wherein: k is n−1; X is abond or CH₂; and Y is a bond or CH₂.
 4. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein R¹ is selected from H,halo, CN, and C₁₋₃ haloalkyl; and R² is selected from C₁₋₃ alkyl andC₁₋₃ haloalkyl; or R¹ is selected from halo, CN, and C₁₋₃ haloalkyl; andR² is selected from H, C₁₋₃ alkyl, and C₁₋₃ haloalkyl.
 5. The compoundof claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹ isselected from H, F, Cl, CN, and CF₃; and R² is selected from CH₃ andCF₃; or R¹ is selected from F, Cl, CN, and CF₃; and R² is selected fromCH₃ and CF₃.
 6. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, wherein R³ is selected from H and C₁₋₃haloalkyl.
 7. The compound of claim 2, or a pharmaceutically acceptablesalt thereof, wherein R³ is selected from H and CF₃.
 8. The compound ofclaim 2, or a pharmaceutically acceptable salt thereof, wherein R⁴ isselected from C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₆ alkyl, 5-6 membered heteroaryl-C₁₋₆ alkyl,(R^(4A))_(o)-phenyl-, and (R⁶)_(p)—C₁₋₆ alkyl-; wherein said C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl, 4-7 membered heterocycloalkyl-C₁₋₆ alkyl, and 5-6membered heteroaryl-C₁₋₆ alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(4A) substituents.
 9. (canceled) 10.The compound of claim 2, or a pharmaceutically acceptable salt thereof,wherein R⁴ is selected from C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, C₃₋₇ cycloalkyl-C₁₋₆alkyl, 4-7 membered heterocycloalkyl-C₁₋₆ alkyl, (R^(4A))_(o)-phenyl-,and (R⁶)_(p)—C₁₋₆ alkyl-; wherein said C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C₃₋₇cycloalkyl-C₁₋₆ alkyl, and 4-7 membered heterocycloalkyl-C₁₋₆ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(4A) substituents.
 11. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, wherein: each R^(4A) is independently selectedfrom halo, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a4), SR^(a4), NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), whereinsaid C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(4B) substituents; each R⁶ isindependently selected from CN, NO₂, OR^(a4), SR^(a4), NHOR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); eachR^(4B) is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41),NR^(c41)R^(d41), NR^(c41)C(O)R^(b41), NR^(c41)S(O)₂R^(b41),S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41); each R^(a4), R^(c4), and R^(d4)is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents; each R^(b4) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4B) substituents; eachR^(a41), R^(c41), and R^(d41) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and each R^(b41) is independently selectedfrom C₁₋₆ alkyl and C₁₋₆ haloalkyl.
 12. (canceled)
 13. The compound ofclaim 2, or a pharmaceutically acceptable salt thereof, wherein: eachR^(4A) is independently selected from halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a4), and NR^(c4)R^(d4); wherein said C₁₋₆ alkyl isoptionally substituted with 1 or 2 independently selected R^(4B)substituents; each R⁶ is independently selected from OR^(a4) andC(O)NR^(c4)R^(d4); each R^(a4), R^(c4), and R^(d4) is independentlyselected from H, C₁₋₆ alkyl, and C₃₋₇ cycloalkyl, wherein said C₁₋₆alkyl and C₃₋₇ cycloalkyl are each optionally substituted with 1 or 2independently selected R^(4B) substituents; each R^(4B) is independentlyselected from H, D, and NR^(c41)R^(d41); each R^(c41) and R^(d41) isindependently selected from H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R^(4C) substituents; or, any R^(c41) and R^(d41)attached to the same N atom, together with the N atom to which they areattached, form a 4-7 membered heterocycloalkyl group, which isoptionally substituted with 1 or 2 independently selected R^(4C)substituents; each R^(4C) is independently selected from H, D, halo, CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl,OR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42),NR^(c42)C(O)OR^(a42), and S(O)₂R^(b42), wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₄ alkyl are each optionallysubstituted by 1 R^(G) group selected from OH and CN; each R^(a42),R^(c42), and R^(d42) is independently selected from H, C₁₋₆ alkyl, andC₁₋₆ haloalkyl; and each R^(b42) is independently selected from C₁₋₆alkyl and C₁₋₆ haloalkyl. 14.-15. (canceled)
 16. The compound of claim2, or a pharmaceutically acceptable salt thereof, wherein Ring moiety Ais azetidin-3-yl, piperidin-3-yl, or piperidin-4-yl.
 17. The compound ofclaim 2, or a pharmaceutically acceptable salt thereof, wherein n is 1or
 2. 18. The compound of claim 2, or a pharmaceutically acceptable saltthereof, wherein R^(b5) is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1 or 2 independently selectedR^(5A) substituents; and each R⁵ is independently selected from H, halo,and C₁₋₂ alkyl.
 19. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, wherein R^(b5) is selected from C₁₋₆ alkyl,C₃₋₇ cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 memberedheteroaryl, phenyl-C₁₋₄ alkyl, and 4-8 membered heterocycloalkyl-C₁₋₄alkyl, which are each optionally substituted with 1 or 2 independentlyselected R^(5A) substituents; and each R⁵ is independently selected fromH, halo, and C₁₋₂ alkyl.
 20. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein each R⁵ isindependently selected from H, F, and CH₃. 21.-22. (canceled)
 23. Thecompound of claim 2, or a pharmaceutically acceptable salt thereof,wherein: each R^(5A) is independently selected from H, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51), C(O)OR^(a51),OC(O)R^(b51), OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),NR^(c51)S(O)₂R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(5B) substituents; each R^(a51), R^(c51), and R^(d51) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(5B) substituents; each R^(b51) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,each of which is optionally substituted with 1, 2, or 3 independentlyselected R^(5B) substituents; each R^(5B) is independently selected fromH, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, OR^(a52), NR^(c52)R^(d52),C(O)R^(b52), C(O)NR^(c52)R^(d52), C(O)OR^(a52), NHC(O)R^(b52),NHS(O)₂R^(b52), NHC(O)OR^(a52), NHC(O)NR^(c52)R^(d52), S(O)₂R^(b52), andS(O)₂NR^(c52)R^(d52); each R^(a52), R^(c52), and R^(d52) isindependently selected from H, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; and eachR^(b52) is independently selected from C₁₋₄ alkyl and C₁₋₄ haloalkyl.24. The compound of claim 2, or a pharmaceutically acceptable saltthereof, wherein: each R^(5A) is independently selected from H, CN, C₁₋₃alkyl, 4-7 membered heterocycloalkyl, OR^(a51), NR^(c51)R^(d51), andNR^(c51)C(O)R^(b51), wherein said C₁₋₃ alkyl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, or 3independently selected R^(5B) substituents; each R^(c51) and R^(d51) isindependently selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; eachR^(b51) is independently selected from 4-7 membered heterocycloalkyl;each R^(5B) is independently selected from H and OR^(a52); and eachR^(a52) is independently selected from H and C₁₋₃ alkyl.
 25. Thecompound of claim 2, or a pharmaceutically acceptable salt thereof,wherein: n is 1 or 2; o is 1 or 2; p is 1 or 2; R¹ is selected from H,halo, CN, and C₁₋₃ haloalkyl; and R² is selected from halo, CN, C₁₋₃alkyl, and C₁₋₃ haloalkyl; or R¹ is selected from halo, CN, and C₁₋₃haloalkyl; and R² is selected from H, halo, CN, C₁₋₃ alkyl, and C₁₋₃haloalkyl; R³ is selected from H, halo, CN, C₁₋₃ alkyl, and C₁₋₃haloalkyl; R⁴ is selected from C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-10membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆alkyl, phenyl-C₁₋₆ alkyl, 4-10 membered heterocycloalkyl-C₁₋₆ alkyl, 5-6membered heteroaryl-C₁₋₆ alkyl, (R^(4A))_(o)-phenyl-, and (R⁶)_(p)—C₁₋₆alkyl-; wherein said C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl, 4-10 membered hetero cycloalkyl-C₁₋₆ alkyl, and 5-6membered heteroaryl-C₁₋₆ alkyl are each optionally substituted by 1, 2,or 3 independently selected R^(4A) substituents. each R⁶ isindependently selected from OR^(a4), SR^(a4), NHOR^(a4), NR^(c4)R^(d4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); each R^(4A) is independentlyselected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl,5-6 membered hetero aryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a4), SR^(a4), NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)₂R^(b4), andS(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, or 3 independently selected R^(4B) substituents; each R^(a4), R^(c4),and R^(d4) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-10 memberedheterocycloalkyl, 5-6 membered hetero aryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-10 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, or 3 independently selected R^(4B) substituents; or, any R^(c4) andR^(d4) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-10 membered heterocycloalkyl group, which isoptionally substituted with 1, 2, or 3 independently selected R^(4B)substituents; each R^(b4) is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl,4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, or 3 independentlyselected R^(4B) substituents; each R^(4B) is independently selected fromH, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),NR^(c41)S(O)₂R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)₂R^(b41), andS(O)₂NR^(c41)R^(d41), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, or 3 independently selected R^(4C) substituents; each R^(a41),R^(c41), and R^(d41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(4C) substituents; or, any R^(c41)and R^(d41) attached to the same N atom, together with the N atom towhich they are attached, form a 4-10 membered heterocycloalkyl group,which is optionally substituted with 1 R^(4C) substituent; each R^(b41)is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, which are each optionally substituted with 1, 2,or 3 independently selected R^(4C) substituents; each R^(4C) isindependently selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a42), SR^(a42), NHOR^(a42),C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42),NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)₂R^(b42), and S(O)₂NR^(c42)R^(d42),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1 R^(G) substituent; each R^(a42),R^(c42), and R^(d42) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1 R^(G) substituent; or, any R^(c42) and R^(d42) attached to the same Natom, together with the N atom to which they are attached, form a 4-7membered heterocycloalkyl group, which is optionally substituted with 1R^(G) substituent; each R^(b42) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1 R^(G) substituent; R^(b5)is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl,4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1 or 2 independently selectedR^(5A) substituents; each R⁵ are independently selected from H, halo,and C₁₋₂ alkyl; each R^(5A) is independently selected from H, CN, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a51), C(O)R^(b51),C(O)NR^(c51)R^(d51), C(O)OR^(a51), OC(O)R^(b51), OC(O)NR^(c51)R^(d51),NR^(c51)R^(d51), NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51),NR^(c51)C(O)NR^(c51)R^(d51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), and S(O)₂NR^(c51)R^(d51),wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(5B) substituents; each R^(a51),R^(c51), and R^(d51) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(5B) substituents; each R^(b51) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, each of which is optionally substitutedwith 1, 2, or 3 independently selected R^(5B) substituents; each R^(5B)is independently selected from H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,OR^(a52), NR^(c52)R^(d52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)OR^(a52), NHC(O)R^(b52), NHS(O)₂R^(b52), NHC(O)OR^(a52),NHC(O)NR^(c52)R^(d52), S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52); eachR^(a52), R^(c52), and R^(d52) is independently selected from H, C₁₋₄alkyl, and C₁₋₄ haloalkyl; each R^(b52) is independently selected fromC₁₋₄ alkyl and C₁₋₄ haloalkyl; and each R^(G) is independently selectedfrom OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇cycloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl,carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy,C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃alkylaminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino.
 26. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein: n is 1 or 2; o is 1or 2; p is 1 or 2; R¹ is selected from H, halo, CN, and C₁₋₃ haloalkyl;and R² is selected from C₁₋₃ alkyl and C₁₋₃ haloalkyl; or R¹ is selectedfrom halo, CN, and C₁₋₃ haloalkyl; and R² is selected from H, C₁₋₃alkyl, and C₁₋₃ haloalkyl; R³ is selected from H and C₁₋₃ haloalkyl; R⁴is selected from C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl, 4-7 membered heterocycloalkyl-C₃₋₆ alkyl, 5-6membered heteroaryl-C₁₋₆ alkyl, (R^(4A))_(o)-phenyl-, and (R⁶)_(p)—C₁₋₆alkyl-; wherein said C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl, 4-7 membered heterocycloalkyl-C₁₋₆ alkyl, and 5-6membered heteroaryl-C₁₋₆ alkyl are each optionally substituted by 1, 2,or 3 independently selected R^(4A) substituents. each R^(4A) isindependently selected from halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,OR^(a4), NR^(c4)R^(d4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl and C₁₋₆haloalkyl is optionally substituted with 1 or 2 independently selectedR^(4B) substituents; each R⁶ is independently selected from OR^(a4),NR^(c4)R^(d4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); each R^(a4), R^(c4), and R^(d4) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered hetero aryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1 or 2 independently selected R^(4B) substituents; each R^(4B) isindependently selected from H, D, CN, OR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41),NR^(c41)R^(d41), NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41),NR^(c41)C(O)NR^(c41)R^(d41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41);each R^(c41) and R^(d41) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4C) substituents; or, any R^(c41) and R^(d41) attached to the same Natom, together with the N atom to which they are attached, form a 4-10membered heterocycloalkyl group, which is optionally substituted with 1or 2 independently selected R^(4C) substituents; each R^(4C) isindependently selected from H, D, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl, OR^(a42), C(O)R^(b42),C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42), OC(O)NR^(c42)R^(d42),NR^(c42)R^(d42), NR^(c42)C(O)R^(b42), NR^(c42)C(O)OR^(a42),NR^(c42)C(O)NR^(c42)R^(d42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)₂R^(b42), and S(O)₂NR^(c42)R^(d42),wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and C₃₋₆cycloalkyl-C₁₋₄ alkyl are each optionally substituted by 1 R^(G)substituent; each R^(a42), R^(c42), and R^(d42) is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; each R^(b42) isindependently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; R^(b5) isselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-10membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl, which are each optionallysubstituted with 1 or 2 independently selected R^(5A) substituents; eachR⁵ are independently selected from H, halo, and C₁₋₂ alkyl; each R^(5A)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51), C(O)OR^(a51), OC(O)R^(b51),OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51), NR^(c51)C(O)R^(b51),NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), and S(O)₂NR^(c51)R^(d51),wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(5B) substituents; each R^(a51),R^(c51), and R^(d51) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(5B) substituents; each R^(b51) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, each of which is optionally substitutedwith 1, 2, or 3 independently selected R^(5B) substituents; each R^(5B)is independently selected from H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,OR^(a52), NR^(c52)R^(d52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)OR^(a52), NHC(O)R^(b52), NHS(O)₂R^(b52), NHC(O)OR^(a52),NHC(O)NR^(c52)R^(d52), S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52); eachR^(a52), R^(c52), and R^(d52) is independently selected from H, C₁₋₄alkyl, and C₁₋₄ haloalkyl; each R^(b52) is independently selected fromC₁₋₄ alkyl and C₁₋₄ haloalkyl; and each R^(G) is independently selectedfrom OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇cycloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl,carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy,C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃alkylaminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino.
 27. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein: n is 1 or 2; o is 1or 2; p is 1 or 2; R¹ is selected from H, F, Cl, CN, and CF₃; and R² isselected from CH₃ and CF₃; or R¹ is selected from F, Cl, CN, and CF₃;and R² is selected from H, CH₃, and CF₃; R³ is selected from H and C₁₋₃haloalkyl; R⁴ is selected from C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, (R^(4A))_(o)-phenyl-,and (R⁶)_(p)—C₁₋₆ alkyl-; wherein said C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, and 4-7 membered heterocycloalkyl-C₃₋₄ alkyl areeach optionally substituted by 1, 2, or 3 independently selected R^(4A)substituents; each R^(4A) is independently selected from halo, CN, C₁₋₆alkyl, C₁₋₆ haloalkyl, OR^(a4), and NR^(c4)R^(d4); wherein said C₁₋₆alkyl is optionally substituted with 1 or 2 independently selectedR^(4B) substituents; each R⁶ is independently selected from OR^(a4) andC(O)NR^(c4)R^(d4); each R^(a4), R^(c4), and R^(d4) is independentlyselected from H, C₁₋₆ alkyl, and C₃₋₇ cycloalkyl, wherein said C₁₋₆alkyl and C₃₋₇ cycloalkyl are each optionally substituted with 1 or 2independently selected R^(4B) substituents; each R^(4B) is independentlyselected from H, D, and NR^(c41)R^(d41); each R^(c41) and R^(d41) isindependently selected from H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R^(4C) substituents; or, any R^(c41) and R^(d41)attached to the same N atom, together with the N atom to which they areattached, form a 4-7 membered heterocycloalkyl group, which isoptionally substituted with 1 or 2 independently selected R^(4C)substituents; each R^(4C) is independently selected from H, D, halo, CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl,OR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42),NR^(c42)C(O)OR^(a42), and S(O)₂R^(b42), wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₄ alkyl are each optionallysubstituted by 1 R^(G) substituent; each R^(a42), R^(c42), and R^(d42)is independently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; eachR^(b42) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkylR^(b5) is selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, 5-6 membered hetero aryl, phenyl-C₁₋₄alkyl, and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, which are eachoptionally substituted with 1 or 2 independently selected R^(5A)substituents; R^(b5) is selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl,phenyl-C₁₋₄ alkyl, and 4-8 membered heterocycloalkyl-C₁₋₄ alkyl, whichare each optionally substituted with 1 or 2 independently selectedR^(5A) substituents; each R⁵ are independently selected from H, halo,and C₁₋₂ alkyl; each R^(5A) is independently selected from H, CN, C₁₋₃alkyl, 4-7 membered heterocycloalkyl, OR^(a51), NR^(c51)R^(d51), andNR^(c51)C(O)R^(b51), wherein said C₁₋₃ alkyl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, or 3independently selected R^(5B) substituents; each R^(c51) and R^(d51) isindependently selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; eachR^(b51) is independently selected from 4-7 membered heterocycloalkyl;each R^(5B) is independently selected from H and OR^(a52); each R^(a52)is independently selected from H and C₁₋₃ alkyl; and each R^(G) isindependently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl,C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₃alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino,C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino,C₁₋₃ alkylaminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino.
 28. The compound of claim 2, having Formula(IIIa):

or a pharmaceutically acceptable salt thereof, wherein k is n−1. 29.-30.(canceled)
 31. The compound of claim 2, having Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein k is 0-1; X¹ is Nor CH; R⁵ is H, F, or CH₃; R¹ is C₁, CF₃, or CN; R^(4A) is CN, CH₃, orhalo; R^(c41) and R^(d41) are each independently selected from H andC₁₋₄ alkyl; or R^(c41) and R^(d41), together with the N atom to whichthey are attached, form a 4-6 membered heterocycloalkyl ring, which isoptionally substituted by one C₁₋₃ alkyl group; and R^(4C) is H, C₁₋₃alkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl, or C(O)(C₁₋₄ alkyl).
 32. The compoundof claim 2, having Formula (V):

or a pharmaceutically acceptable salt thereof, wherein k is 0-1; R⁵ isH, F, or CH₃; R¹ is CF₃ or CN; and R^(a4) is H or C₁₋₃ alkyl.
 33. Thecompound of claim 2, having Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein k is 0-1; R⁵ isH, F, or CH₃; and R¹ is CF₃ or CN.
 34. The compound of claim 2, selectedfrom:N-(1-((1-Methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(1-((1H-Pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(1-(Methylsulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;2-((4-((4-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)acetonitrile;N-(1-(Benzylsulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-N-(1-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;3-((4-((4-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile;N-(4-((4-((4-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)morpholine-4-carboxamide;N-(1-((1-Methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(1-(Methylsulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-Cyclohexyl-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(2-Fluorophenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(2-Chlorophenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;5-Fluoro-4-(3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine;4-(3-Methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine;5-Fluoro-4-(1-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine;4-(1-(1-Methylpiperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;(±)-N-(1-(Methylsulfonyl)piperidin-3-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(1-(Methylsulfonyl)azetidin-3-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;(±)-N-((2S,4R)-2-Methyl-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;and5-Chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine;or a pharmaceutically acceptable salt thereof.
 35. The compound of claim2, selected from:N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(1-((1-Ethyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;trans-4-(4-(2-((1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol;3-Chloro-4-(4-(2-(1-(methylsulfonyl)piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzonitrile;N-(cis-3-Hydroxy-1-methylcyclobutyl)-6-methyl-5-(4-(2-(1-(methylsulfonyl)piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)picolinamide;4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;2-Methyl-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanamide;4-(1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;(R)—N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;trans-4-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclohexane-1-carbonitrile;4-(1-(2-Amino-3-methylpyridin-4-yl)-H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(2-Amino-3-chloropyridin-4-yl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(2-Amino-5-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;2-((1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;2-((1-(Pyridin-2-ylsulfonyl)piperidin-4-yl)amino)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;and5-Chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-amine;or a pharmaceutically acceptable salt thereof.
 36. The compound of claim2, selected from:4-(1-(2-Methyl-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-((1r,4r)-4-Methoxycyclohexyl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-((3R,4S)-3-Fluoro-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-((trans)-4-methoxycyclohexyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-((1 s,3s)-3-Amino-3-methylcyclobutyl)-1H-pyrazol-4-yl)-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-((1s,3s)-3-Amino-3-methylcyclobutyl)-1H-pyrazol-4-yl)-N-(1-(isopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-((1s,3s)-3-Amino-3-methylcyclobutyl)-1H-pyrazol-4-yl)-N-(1-(cyclobutylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-((1s,3r)-3-Amino-3-methylcyclobutyl)-1H-pyrazol-4-yl)-N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-((1s,3r)-3-Amino-3-methylcyclobutyl)-1H-pyrazol-4-yl)-N-((3R,4S)-1-(cyclobutylsulfonyl)-3-fluoropiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-((1s,3s)-3-(Methylamino)cyclobutyl)-1H-pyrazol-4-yl)-N-(1-(pyridin-2-ylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-((1r,3r)-3-(Methylamino)cyclobutyl)-1H-pyrazol-4-yl)-N-(1-(pyridin-2-ylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;1-(4-(2-((1-(Cyclopropylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;2-Methyl-1-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;1-(4-(2-((1-(Ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;2-((1-(Cyclopropylsulfonyl)piperidin-4-yl)amino)-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;l-(4-(5-Chloro-2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-(((3R,4S)-1-(Cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-(((3R,4S)-1-(Cyclopropylsulfonyl)-3-methylpiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;2-Methyl-1-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;2-Methyl-1-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;2-Methyl-1-(4-(2-(((3R,4S)-3-methyl-1-(pyridin-2-ylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;2-Methyl-1-(4-(2-((1-((3-morpholinopropyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;1-(4-(2-((1-((3-(Diethylamino)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-((1-((3-(Azetidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;2-Methyl-1-(4-(2-((1-((3-(pyrrolidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;2-Methyl-1-(4-(2-((1-((3-(piperidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;2-Methyl-1-(4-(2-((1-((3-(4-methylpiperazin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;4-(3-((4-((4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)propyl)piperazin-2-one;4-(3-((4-((4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)propyl)-1-methylpiperazin-2-one;(S)-2-Methyl-1-(4-(2-((1-((3-(3-methylmorpholino)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;(R)-2-Methyl-1-(4-(2-((1-((3-(3-methylmorpholino)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;1-(4-(2-((1-((3-(7-Oxa-4-azaspiro[2.5]octan-4-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;(S)-1-(4-(2-((1-((3-(3-(Methoxymethyl)pyrrolidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(3-((4-((4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)propyl)piperidin-4-ol;1-(3-((4-((4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)propyl)piperidine-4-carbonitrile;1-(4-(2-((1-((3-(4-Methoxypiperidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-((1-((4-(Dimethylamino)butyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-((1-((4-(Diethylamino)butyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;2-Methyl-1-(4-(2-((1-((4-(pyrrolidin-1-yl)butyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;2-Methyl-1-(4-(2-((1-((4-(piperidin-1-yl)butyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;2-Methyl-1-(4-(2-((1-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;1-(4-(2-((1-((2-(Dimethylamino)ethyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;2-Methyl-1-(4-(2-((1-((2-morpholinoethyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;2-Methyl-1-(4-(2-((1-((1-methylazetidin-3-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;(±)-2-Methyl-1-(4-(2-((1-((1-methylpyrrolidin-3-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;2-Methyl-1-(4-(2-((1-((1-methylpiperidin-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;1-(4-(2-((1-((4-(Dimethylamino)cyclohexyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-((1-((4-(Diethylamino)cyclohexyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-((1-((4-(Azetidin-1-yl)cyclohexyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;2-Methyl-1-(4-(2-((1-((4-(pyrrolidin-1-yl)cyclohexyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;3-((4-((4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)propan-1-ol;4-((4-((4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)butan-1-ol;4-((4-((4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-methylbutan-2-ol;(±)-1,1,1-Trifluoro-2-methyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol;2-Methyl-2-(4-(2-((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanamide;2-(4-(2-((1-(Ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide;2-(4-(2-((1-(Cyclopropylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide;4-(1-(2-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-((3R,4S)-3-Fluoro-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(3R,4S)-3-Fluoro-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;1-(4-(4-(4-(2-(((3R,4S)-3-Fluoro-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-methylbenzyl)piperazin-1-yl)ethan-1-one;1-(4-(3-Methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)piperazin-1-yl)ethan-1-one;4-(1-(4-((Dimethylamino)methyl)-2-methylphenyl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-(morpholinomethyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;5-Chloro-4-(1-(2-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)pyrimidin-2-amine;5-Chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)pyrimidin-2-amine;5-Chloro-N-(1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)pyrimidin-2-amine;4-(1-(2-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((ethylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-1-(ethylsulfonyl)-3-fluoropiperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-3-fluoro-1-(propylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-3-fluoro-1-(isopropylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-1-(cyclobutylsulfonyl)-3-fluoropiperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-1-((3-cyanopropyl)sulfonyl)-3-fluoropiperidin-4-yl)amino)pyrimidine-5-carbonitrile;N-((3R,4S)-1-(Cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)-4-(1-(2-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;5-Chloro-4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine;4-(1-(6-((Ethylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;2-((1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-4-(1-(2-methyl-6-((methylamino)methyl)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;4-(1-(6-((Ethylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Methyl-4-(((methyl-d₃)amino)methyl)phenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(1-(Ethylsulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(1-((1-Methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(3R,4S)-1-(Cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)-4-(1-(2-methyl-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;5-Chloro-4-(1-(2-chloro-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine;5-Chloro-4-(1-(2-chloro-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)pyrimidin-2-amine;5-Chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)pyrimidin-2-amine;5-Chloro-N-(1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)pyrimidin-2-amine;4-(1-(2-Chloro-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((methyl-d3)amino)methyl-d)phenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-1-(ethylsulfonyl)-3-fluoropiperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((methyl-d3)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;2-((1-((1-Methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-4-(1-(2-methyl-6-(((methyl-d3)amino)methyl)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;2-(((3R,4S)-3-Methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-4-(1-(2-methyl-6-(((methyl-d3)amino)methyl)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;4-(1-(6-((Isopropylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(6-((tert-Butylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;2-((1-(Cyclopropylsulfonyl)piperidin-4-yl)amino)-4-(1-(6-((isopropylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1s,3s)-3-cyanocyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-chloro-4-((((1 r, 3 r)-3-hydroxy-1-methylcyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1-hydroxycyclopropyl)methyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((1-hydroxy-2-methylpropan-2-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1s,3s)-3-hydroxy-1-methylcyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;2-((3-Chloro-4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)amino)-2-methylpropanamide;4-(1-(2-Chloro-4-((((1r,3r)-3-hydroxycyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1s,3s)-3-hydroxycyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1s,3s)-3-methoxycyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1s,3s)-3-cyanocyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((1-methyl-1H-pyrazol-4-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;Methyl(2-((3-chloro-4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)amino)cyclohexyl)carbamate;Methyl(S)-3-((3-chloro-4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)amino)piperidine-1-carboxylate;Methyl(R)-3-((3-chloro-4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)amino)piperidine-1-carboxylate;(S)-4-(1-(4-(((1-Acetylpyrrolidin-3-yl)amino)methyl)-2-chlorophenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;(R)-4-(1-(4-(((1-Acetylpyrrolidin-3-yl)amino)methyl)-2-chlorophenyl)-1H-pyrazol-4-y1)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(4-(((1-Acetylazetidin-3-yl)amino)methyl)-2-chlorophenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;Methyl3-((3-chloro-4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)amino)azetidine-1-carboxylate;4-(1-(2-Chloro-4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1R,2R)-2-hydroxycyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1R,2S)-2-hydroxycyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1S,3R)-3-hydroxycyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1S,3S)-3-hydroxycyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1r,4r)-4-hydroxycyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((4-cyanocyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((2-(dimethylamino)cyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((cis)-4-(methylsulfonyl)cyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1R,2R)-2-hydroxycyclopentyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1S,2S)-2-hydroxycyclopentyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1S,3R)-3-hydroxycyclopentyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1R,3R)-3-hydroxycyclopentyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1 r,3r)-3-hydroxy-3-methylcyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1-ethyl-1H-pyrazol-4-yl)methyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;(R)-4-(1-(2-Chloro-4-(((tetrahydro-2H-pyran-3-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;(S)-4-(1-(2-Chloro-4-(((tetrahydro-2H-pyran-3-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;Ethyl4-((3-chloro-4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)amino)piperidine-1-carboxylate;(±)-4-(1-(2-Chloro-4-(((1-(methylsulfonyl)pyrrolidin-3-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((2-(trifluoromethoxy)ethyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((2-(methylsulfonyl)ethyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;1-(4-(2-(((3R,4S)-3-Fluoro-1-((3-morpholinopropyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-(((3R,4S)-1-((3-(Diethylamino)propyl)sulfonyl)-3-fluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-(((3N4S)-3-Fluoro-1-((3-(pyrrolidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-(((3N4S)-3-Fluoro-1-((3-(piperidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-(((3R,45)-1-((3-(Dimethylamino)propyl)sulfonyl)-3-fluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-(((3R,4S)-3-Fluoro-1-((3-((R)-3-methoxypyrrolidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-(((3R,4S)-3-Fluoro-1-((3-(4-methoxypiperidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(3-(((3R,4S)-3-Fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)propyl)piperidin-4-ol;1-(4-(2-(((3R,4S)-3-Fluoro-1-((3-(4-methylpiperazin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-(((3R,4S)-1-((3-(4-Ethylpiperazin-1-yl)propyl)sulfonyl)-3-fluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-(((3N4S)-3-Fluoro-1-((3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;4-(3-(((3R,4S)-3-Fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)propyl)-1-methylpiperazin-2-one;2-((1-((3-(Diethylamino)propyl)sulfonyl)piperidin-4-yl)amino)-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-((1-((3-(pyrrolidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-((1-((3-(piperidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;2-((1-((4-(Diethylamino)butyl)sulfonyl)piperidin-4-yl)amino)-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-((1-((4-(pyrrolidin-1-yl)butyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-((1-((4-(piperidin-1-yl)butyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;(S)-1-(4-(2-((1-((3-(3-Methoxypyrrolidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;(R)-1-(4-(2-((1-((3-(3-Methoxypyrrolidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;(S)-1-(4-(2-((1-((3-(2-(Methoxymethyl)azetidin-1-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-((1-((3-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;(R)-1-(3-((4-((4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)propyl)-3-methylpyrrolidin-3-ol;(R)-1-(3-((4-((4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)propyl)pyrrolidin-3-ol;1-(3-((4-((4-(1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)propyl)azetidin-3-ol;1-(4-(2-((1-((3-(Cyclopropylamino)propyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;1-(4-(2-((1-((2-Hydroxyethyl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-(piperazin-1-ylmethyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;(R)-(1-Methyl-4-(3-methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)piperazin-2-yl)methanol;(S)-2-(1-Methyl-4-(3-methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)piperazin-2-yl)acetonitrile;4-(1-(2-Methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(4-((4-Ethylpiperazin-1-yl)methyl)-2-methylphenyl)-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(1-(Ethylsulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-4-(1-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(4-((4-Ethylpiperazin-1-yl)methyl)-2-methylphenyl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(4-((4-(Cyclopropylmethyl)piperazin-1-yl)methyl)-2-methylphenyl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;1-Methyl-4-(3-methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)piperazin-2-one;4-(1-(2-Chloro-4-((4-ethylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((4-methyl-3-oxopiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((4-ethylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;2-((1-(Cyclopropylsulfonyl)piperidin-4-yl)amino)-4-(1-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;2-((1-((1-Methyl-1H-imidazol-4-y 1)sulfonyl)piperidin-4-yl)amino)-4-(1-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;2-(4-(5-Chloro-2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-5-((4-methylpiperazin-1-yl)methyl)benzonitrile;5-Chloro-4-(1-(4-((4-ethylpiperazin-1-yl)methyl)-2-methylphenyl)-1H-pyrazol-4-y1)-A-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)pyrimidin-2-amine;5-Chloro-4-(1-(4-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)-2-methylphenyl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)pyrimidin-2-amine;5-Chloro-4-(1-(4-((4-isopropylpiperazin-1-yl)methyl)-2-methylphenyl)-1H-pyrazol-4-y1)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)pyrimidin-2-amine;4-(4-(4-(5-Chloro-2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-methylbenzyl)-1-methylpiperazin-2-one;5-Chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine;5-Chloro-4-(1-(6-((4-ethylpiperazin-1-yl)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)pyrimidin-2-amine;5-Chloro-4-(1-(6-((4-isopropylpiperazin-1-yl)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)pyrimidin-2-amine;N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(6-((4-Ethylpiperazin-1-yl)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(6-((4-Isopropylpiperazin-1-yl)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(6-((4-Ethylpiperazin-1-yl)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(6-((4-Isopropylpiperazin-1-yl)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(2-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(6-((tert-Butylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(6-(((2-Cyclopropylpropan-2-yl)amino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;2-(((5-(4-(5-Cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl)methyl)amino)-2-methylpropanamide;4-(1-(6-((((1s,3s)-3-Hydroxy-1-methylcyclobutyl)amino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;5-Chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-6-((methylamino)methyl)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine;5-Chloro-4-(1-(6-((ethylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)pyrimidin-2-amine;N-(1-((1-Methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-6-((methylamino)methyl)pyridin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(6-((Ethylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;N-(3R,4S)-3-Methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-4-(1-(2-methyl-6-((methylamino)methyl)pyridin-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(6-((Ethylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;2-(((3R,4S)-3-Methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-4-(1-(2-methyl-6-((methylamino)methyl)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;4-(1-(6-((Ethylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;5-Chloro-4-(1-(6-((isopropylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)pyrimidin-2-amine;4-(1-(6-((Isopropylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(6-((Isopropylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;4-(1-(6-((tert-Butylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(6-((Isopropylamino)methyl)-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;Methyl((1R,3R)-3-((3-chloro-4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)amino)cyclopentyl)carbamate;Methyl((1S,3R)-3-((3-chloro-4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)amino)cyclopentyl)carbamate;Methyl((1S,2S)-2-((3-chloro-4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)amino)cyclopentyl)carbamate;Methyl((1-((3-chloro-4-(4-(5-cyano-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)benzyl)amino)cyclopentyl)methyl)carbamate;4-(1-(2-Chloro-4-((((1S,4S)-4-hydroxy-4-methylcyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1r,3s)-3-hydroxy-3-methylcyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;(±)-4-(1-(2-Chloro-4-((((1r,2r)-2-hydroxy-2-methylcyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(ethylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-((((1R,2S)-2-hydroxycyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-chloro-4-((((1s,4s)-4-(hydroxymethyl)cyclohexyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;4-(1-(2-Chloro-4-(((2-(1,1-dioxidothiomorpholino)ethyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;(R)-4-(1-(2-Chloro-4-(((2-hydroxypropyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;and(S)-4-(1-(2-Chloro-4-(((2-hydroxypropyl)amino)methyl)phenyl)-1H-pyrazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile;or a pharmaceutically acceptable salt thereof.
 37. A pharmaceuticalcomposition comprising a compound of claim 2, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 38.A method of inhibiting CDK2, comprising contacting the CDK2 with acompound of claim
 2. 39. A method of inhibiting CDK2 in a patient,comprising administering to the patient a compound of claim 2, or apharmaceutically acceptable salt thereof.
 40. A method of treating adisease or disorder associated with CDK2 in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of claim 2, or pharmaceutically acceptable salt thereof,wherein the disease or disorder is associated with an amplification ofthe cyclin E1 (CCNE1) gene and/or overexpression of CCNE1.
 41. A methodof treating a human subject having a disease or disorder associated withcyclin-dependent kinase 2 (CDK2), comprising administering to the humansubject a compound of claim 2, or a pharmaceutically acceptable saltthereof, wherein the human subject has been previously determined to:(i) (a) have a nucleotide sequence encoding a p16 protein comprising theamino acid sequence of SEQ ID NO: 1; and/or (b) have a cyclin dependentkinase inhibitor 2A (CDKN2A) gene lacking one or more inactivatingnucleic acid substitutions and/or deletions; (ii) (a) have anamplification of the cyclin E1 (CCNE1) gene; and/or (b) have anexpression level of CCNE1 in a biological sample obtained from the humansubject that is higher than a control expression level of CCNE1.
 42. Amethod of treating a human subject having a disease or disorderassociated with cyclin-dependent kinase 2 (CDK2), comprising: (i)identifying, in a biological sample obtained from the human subject: (a)a nucleotide sequence encoding a p16 protein comprising the amino acidsequence of SEQ ID NO:1; and/or (b) a cyclin dependent kinase inhibitor2A (CDKN2A) gene lacking one or more inactivating nucleic acidsubstitutions; (ii) identifying, in a biological sample obtained fromthe human subject: (a) an amplification of the cyclin E1 (CCNE1) gene;and/or (b) an expression level of CCNE1 that is higher than a controlexpression level of CCNE1; and (iii) administering a compound of claim2, or a pharmaceutically acceptable salt thereof, to the human subject.43. The method of claim 42, comprising: (i) identifying, in a biologicalsample obtained from the human subject: (a) a nucleotide sequenceencoding a p16 protein comprising the amino acid sequence of SEQ IDNO:1; and/or (b) a CDKN2A gene lacking one or more inactivating nucleicacid substitutions and/or deletions; (ii) identifying, in a biologicalsample obtained from the human subject: (a) an amplification of theCCNE1 gene; and (iii) administering the compound or the salt to thehuman subject.
 44. A method of evaluating the response of a humansubject having a disease or disorder associated with cyclin-dependentkinase 2 (CDK2) to a compound of claim 2, or a pharmaceuticallyacceptable salt thereof, comprising: (a) administering the compound orthe salt, to the human subject, wherein the human subject has beenpreviously determined to have an amplification of the cyclin E1 (CCNE1)gene and/or an expression level of CCNE1 that is higher than a controlexpression level of CCNE1; (b) measuring, in a biological sample ofobtained from the subject subsequent to the administering of step (a),the level of retinoblastoma (Rb) protein phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3, wherein areduced level of Rb phosphorylation at the serine corresponding to aminoacid position 780 of SEQ ID NO:3, as compared to a control level of Rbphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3, is indicative that the human subject responds to thecompound or the salt.
 45. The method of claim 40, wherein the disease ordisorder is cancer.